ES2382712T3 - 4-Oxadiazolyl-piperidine compounds and use thereof - Google Patents

Abstract

4-Oxadiazolyl-piperidine compounds of formula (I) and (II), their compositions and use for the treatment of pain and diarrhoea.

Description

4-Oxadiazolyl-piperidine compounds and use thereof

1. Field of the invention

[0001] The present invention relates to 4-oxadiazolyl-piperidine Compounds, to compositions comprising a 4-oxadiazolyl-piperidine Compound and to its use for preventing or treating pain or diarrhea in an animal, which comprises administering an effective amount of a 4-oxadiazolyl-piperidine compound to an animal that needs such prevention

or treatment

2. Background of the invention

[0002] Pain is the most common symptom for which patients seek medical advice and treatment. The pain can be acute or chronic. While acute pain is usually self-limited, chronic pain can persist for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability or overall quality of life (KM Foley , Pain, in Cecil Textbook of Medicine 100107, eds. JC Bennett and F. Plum, ed. 20ª 1996).

[0003] Pain has traditionally been treated by administering a non-opioid analgesic, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal and naproxen; or an opioid analgesic, such as morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone and oxymorphone. Id.

[0004] United States Patent No. 6,576,650 B1, United States Patent 6,166,039, and United States Patent No. 5,849,761, issued to Yaksh, and United States Patent n. No. 6,573,282, issued to Yaksh et al., Discloses 1,4-substituted piperidine derivatives purportedly useful as peripherally active antihyperalgesic opioids.

[0005] US Patent No. 6,362,203 B1 issued to Mogi et al. describes 4-hydroxy-4-phenylpiperidine derivatives that are supposed to have a peripheral analgesic action.

[0006] Canadian Patent Publication No. 949560 of Carron et al. describes piperidine derivatives that carry substituents at positions 1 and 4, which are supposed to be useful as analgesics.

[0007] International Publication No. WO 02/38185 A2 by Dunn et al. describes 1,4 substituted piperidine compounds that are supposedly useful as antihyperalgesic opiates.

[0008] The abstract of International Publication No. WO 01/70689 A1 also discloses piperidine derivatives which carry substituents at positions 1 and 4 and which are supposedly useful as agonists of opioid receptors 8.

[0009] WO 2004/046 132 describes 4-tetrazolyl piperidine compounds with the same activity.

[0010] Traditional opioid analgesics exert their pharmacological activity once they have passed through the blood brain barrier. However, this passage through the blood-brain barrier can lead to undesirable side effects mediated by the central nervous system, such as respiratory depression, increased drug tolerance, increased drug dependence, constipation and unwanted euphoria.

[0011] There is still an obvious need for new drugs that are useful for treating or preventing pain or diarrhea and that reduce or avoid one or more of the side effects associated with traditional therapy for the treatment of pain or diarrhea.

3. Summary of the invention [0012] The present invention encompasses compounds having the formula (I):

and pharmaceutically acceptable salts thereof, wherein: [0013] Ar1 is phenyl, which is unsubstituted or substituted with one, two, or three R2 groups; [0014] Ar2 is phenyl, which is unsubstituted or substituted with one, two, or three R2 groups; [0015] Ar4 is phenyl, which is unsubstituted or substituted with one, two, or three R2 groups; [0016] G is -H, -C (O) (CH2) nCO2R4, -C (O) (CH2) nR5, - (C1-C5 alkylene) CO2R4, or - (C1-C5 alkylene) R5; [0017] R1 = -H, -C (O) NH2, -C (O) NHOH, -CO2R4, -CHO, -CN, - (C1-C4 alkyl), -C (O) NH (C1-C4 alkyl ), -C (O) N (C1 alkyl

C4) 2, -CF3, -CHF2, -CH2F,

[0019] R4 = -H, -C1-C10 alkyl, -CH2O (C1-C4 alkyl), -CH2N (C1-C4 alkyl) 2, or -CH2NH (C1-C4 alkyl);

[0020] R5 = -NH2, -NHSO2R4, -C (O) NH2, -C (O) NHOH, -SO2NH2, -C (O) NH (C1-C4 alkyl), -C (O) N (C1 alkyl -C4) 2, SO2NH (C1-C4 alkyl), -SO2N (C1-C4 alkyl) 2, -H, -OH, -CN, or -C3-C8 cycloalkyl, phenyl, naphthyl, anthropyl, phenanthryl, heteroaryl (5 7 members), not being substituted or being substituted with one or more R2 groups each C3-C8 cycloalkyl, phenyl, naphthyl, antryl, phenanthryl, heteroaryl (5 to 7 members);

m = an integer that goes from 0 to 4;

n = an integer ranging from 1 to 4;

p = 0 or 1; Y

q = an integer ranging from 1 to 6.

[0021] The present invention also encompasses compounds having the formula (II):

and pharmaceutically acceptable salts thereof, wherein: [0022] Ar3 is phenyl, which is unsubstituted or substituted with one, two, or three R2 groups; [0023] Ar4 is phenyl, which is unsubstituted or substituted with one, two, or three R2 groups; [0024] G = H, -C (O) (CH2) nC (O) OR4, -C (O) (CH2) nR5, - (C1-C5 alkylene) COOR4, or - (C1-C5 alkylene) R5; [0025] R1 = -H, -C (O) NH2, -C (O) NHOH, -CO2R4, -CHO, -CN, - (C1-C4 alkyl), -C (O) NH (C1-C4 alkyl ), -C (O) N (C1- alkyl

C4), -CF3, -CHF2, -CH2F,

or

[0026] R2 and R3 are each independently -halogen, -C1-C3 alkyl, -O (C1-C3 alkyl), -NH (C1-C3 alkyl), N (C1-C3 alkyl) 2, -CF3, or -OCF3;

[0027] R4 = -H, -C1-C10 alkyl, -CH2O (C1-C4 alkyl), -CH2N (C1-C4 alkyl) 2, or -CH2NH (C1-C4 alkyl);

[0028] R5 = -NH2, -NHSO2R4, -C (O) NH2, -C (O) NHOH, -SO2NH2, -C (O) NH (C1-C4 alkyl), -C (O) N (C1 alkyl -C4) 2, SO2NH (C1-C4 alkyl), -SO2N (C1-C4 alkyl) 2, -H, -OH, -CN, or -C3-C8 cycloalkyl, phenyl, naphthyl, anthropyl, phenanthryl, heteroaryl (5 7 members), not being substituted or being substituted with one or more R2 groups each C3-C8 cycloalkyl, phenyl, naphthyl, antryl, phenanthryl, heteroaryl (5 to 7 members);

m = an integer that goes from 0 to 4;

n = an integer ranging from 1 to 4;

p = 0 or 1; Y

q = an integer ranging from 1 to 6.

[0029] A compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof (each being a "4-oxadiazolyl-piperidine compound") is useful for treating or preventing pain or diarrhea in an animal.

[0030] The invention also relates to compositions comprising a 4-oxadiazolyl-piperidine Compound and a pharmaceutically acceptable carrier or excipient. The present compositions are useful for treating or preventing pain or diarrhea in an animal.

[0031] The invention also relates to kits comprising a package containing an effective amount of a 4-oxadiazolyl-piperidine Compound and instructions for use with a view to treating or preventing pain or diarrhea.

[0032] The invention further relates to a 4-oxadiazolyl-piperidine Compound for use in the prevention of pain or diarrhea in an animal, which comprises administering an effective amount of a 4-oxadiazolylpiperidine Compound to an animal which need. In other aspects of this embodiment, these uses for preventing pain or diarrhea in an animal further comprise administering an effective amount of an opioid analgesic, a non-opioid analgesic, an anti-emetic agent, or a combination thereof.

[0033] The invention further relates to a 4-oxadiazolyl-piperidine Compound for use in the treatment of pain or diarrhea in an animal, which comprises administering an effective amount of a 4-oxadiazolylpiperidine Compound to an animal which need. In other aspects of this embodiment, these uses for treating pain or diarrhea in an animal further comprise administering an effective amount of an opioid analgesic, a non-opioid analgesic, an anti-emetic agent, or a combination thereof.

[0034] The invention also relates to the use of a 4-oxadiazolyl-piperidine Compound in the preparation of a medicament useful for treating or preventing pain or diarrhea.

[0035] The invention still further relates to the use of a compound according to the invention, in the preparation of a medicament for stimulating the function of opioid receptors in a cell, which comprises bringing into contact a cell capable of expressing a opioid receptor with a 4-oxadiazolylpiperidine Compound.

[0036] The invention still further relates to methods for preparing a pharmaceutical composition, comprising the step in which a 4-oxadiazolyl-piperidine Compound is mixed with a pharmaceutically acceptable carrier or excipient.

[0037] The present invention can be understood in more detail by referring to the detailed description and following illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.

4. Detailed description of the invention

4.1 Definitions

[0038] As used herein, the expressions used above have the following meaning:

[0039] "-C1-C3 alkyl" means a straight or branched chain of non-cyclic hydrocarbon having between 1 and 3 carbon atoms. Representative C1-C3-straight and branched-chain alkyl include -methyl, -ethyl, -n-propyl and isopropyl.

[0040] "-C1-C4 alkyl" means a straight or branched chain of non-cyclic hydrocarbon having between 1 and 4 carbon atoms. Representative C1-C4 straight chain alkyl include methyl, -ethyl, -n-propyl, and -n-butyl. Representative branched-chain C1-C4 alkyl include -isopropyl, -sec-butyl, -isobutyl and -tert-butyl.

[0041] "-C1-C6 alkyl" means a straight or branched chain of non-cyclic hydrocarbon having between 1 and 6 carbon atoms. Representative C1-C6 straight chain alkyl include methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl. Representative branched-chain C1-C6 alkyl include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1 -Dimethylpropyl, 1,2- dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1- dimethylbutyl, 1,2-dimethylbutyl, 1 , 3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylbutyl.

[0042] "-C1-C10 alkyl" means a non-cyclic straight or branched chain hydrocarbon having between 1 and 10 carbon atoms. Representative linear-chain (C1-C10) alkyls include methyl, -methyl, -n-propyl, -n- butyl, -n-pentyl, -n-hexyl, -n-heptyl -n-octyl, –N – nonyl, and –n – decyl. Representative branched (C1-C10) alkyl include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2 –Dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1– ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2 , 2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1 , 2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

[0043] "-C1-C5 alkylene" means a divalent, non-cyclic, straight or branched chain hydrocarbon having between 1 and 5 carbon atoms. Among the groups –C1-C5 alkylene linear straight chain are –CH2–, - (CH2) 2–, - (CH2) 3–, - (CH2) 4– and - (CH2) 5–. Representative branched C2-C5 alkylene groups include CH (CH3) -, –C (CH3) 2–, –CH (CH3) CH2–, –CH2CH (CH3) -, –CH2C (CH3) 2–, - C (CH3) 2CH2–, –CH (CH3) CH (CH3) -, - CH2C (CH3) 2CH2–, - (CH2) 2C (CH3) 2–, - (CH3) 2 (CH2) 2C– and –CH (CH3) CH2CH (CH3) -.

[0044] "-C3-C8 cycloalkyl" means a saturated cyclic hydrocarbon having between 3 and 8 carbon atoms. Among the representative C3-C8 cycloalkyl are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and -cyclooctyl.

[0045] "-heteroaryl (5 to 7 members)" means an aromatic heterocyclic ring of 5 to 7 members, in which at least one carbon atom of the ring is substituted with a heteroatom independently selected from nitrogen , oxygen and sulfur. The heteroaryl ring (5 to 7 members) contains at least one carbon atom. Representative - heteroaryls (5 to 7 members) include pyridyl, furyl, thiophenyl, pyrrolyl, oxadiazolyl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl and triazinyl.

[0046] "-Halogen" means -F, -Cl, -Br, or -I.

[0047] The term "animal" includes, but is not limited to, cows, apes, monkeys, chimpanzees, baboons, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, Guinea pigs and humans.

[0048] The term "pharmaceutically acceptable salt", as used herein, is a salt formed from an acid and the basic nitrogen group of a 4-oxadiazolyl-piperidine Compound. Illustrative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate salts, oleate, tanate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, sucrate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e. 1.1 ' - methylene-bis- (2-hydroxy-3-naphthoate)). The term "pharmaceutically acceptable salt" also refers to a salt of a 4-oxadiazolyl-piperidine Compound having an acid functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Illustrative bases include, but are not limited to, alkali metal hydroxides such as sodium, potassium, and lithium; alkaline earth metal hydroxides such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia; and organic amines, such as mono-, di-, or unsubstituted or hydroxy-substituted trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl-N-ethylamine; diethylamine; triethylamine; mono–, bis–, or tris– (2-hydroxy alkyl short chain amines), such as mono–, bis–, or tris– (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine, or tris– ( hydroxymethyl) methylamine, N, N-di-alkyl (short chain) -N- (hydroxy alkyl (short chain)) - amines, such as N, N-dimethyl-N- (2-hydroxyethyl) amine, or tri- ( 2– hydroxyethyl) amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine and the like.

[0049] The terms "treat", "treatment of" and "treating" pain or diarrhea include decreased severity,

or the cessation of pain or diarrhea. In one of the embodiments, the terms "treat", "treating" or "treatment of" include the inhibition, for example the reduction, of the overall frequency of episodes of pain or diarrhea, respectively.

[0050] The terms "prevent", "prevention of" and "preventing" pain or diarrhea include the avoidance of

appearance of pain or diarrhea, respectively.

[0051] The term "opioid receptor" means an opioid receptor 8, an opioid receptor K, an opioid receptor 1 or a ORL-1 receiver. [0052] The term "effective amount" when used in connection with a Compound of 4'-oxadiazolyl-piperidine

means an amount of the 4-oxadiazolyl-piperidine compound that is useful for treating or preventing pain or diarrhea

in an animal or stimulate the function of opioid receptors in a cell. [0053] The term "effective amount" when used in relation to another therapeutic agent means a useful amount. to provide the therapeutic effect of that particular therapeutic agent.

[0054] When a first group is "replaced with one or more" second groups, each of one or more of the Hydrogen atoms of the first group are substituted with a second group. [0055] In one of the embodiments, a first group is replaced with up to three second groups. [0056] In another embodiment, a first group is replaced with one or two second groups. [0057] In another embodiment, a first group is replaced with only a second group.

4. 2 Compounds of 4-oxadiazolyl-piperidine

[0058] As mentioned above, the present invention encompasses 4-oxadiazolyl-piperidine compounds having the formula (1):

and pharmaceutically acceptable salts thereof, wherein Ar1, Ar2, Ar4, R1-R3, G, n, m, p and q are as defined above.

[0059] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G is -H.

[0060] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G is C (O) (CH2) nCO2R4.

[0061] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G is -C (O) (CH2) nC (O) OH.

[0062] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G is C (O) (CH2) nC (O) OR4 and R4 = -C1-C10 alkyl.

[0063] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G is C (O) (CH2) nC (O) OR4 and R4 = -CH2O (C1-C4 alkyl) .

[0064] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G is C (O) (CH2) nC (O) OR4 and R4 = -CH2NH (C1-C4 alkyl) or -CH2N (C1-C4 alkyl) 2.

[0065] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (-C1-C5 alkylene) C (O) OR4.

[0066] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = CH2C (O) OR4.

[0067] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = CH2C (O) OCH2CH3.

[0068] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 2C (O) OR4.

[0069] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 3C (O) OR4.

[0070] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 4C (O) OR4.

[0071] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 5C (O) OR4.

[0072] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G is C (O) (CH2) nR5 and R5 = -NHSO2R4.

[0073] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G is C (O) (CH2) nR5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O) NH (C1-C4 alkyl), or C- (O) N (C1-C4 alkyl) 2.

[0074] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G is C (O) (CH2) nR5 and R5 = -SO2NH2, -SO2NH (C1-C4 alkyl), or -SO2N (C1-C4 alkyl) 2.

[0075] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G is C (O) (CH2) nR5 and R5 = -NHSO2H.

[0076] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (C1-C5 alkylene) R5.

[0077] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = -CH2-R5

.

[0078] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 2-R5.

[0079] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 3-R5.

[0080] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 4-R5.

[0081] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 5-R5.

[0082] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (C1-C5 alkylene) R5 and R5 = -C (O) NH2, -C (O) NHOH , -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2.

[0083] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = -CH2R5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O ) NH (C1-C4 alkyl), or C (O) N (C1-C4 alkyl) 2.

[0084] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = -CH2C (O) N (CH3) 2.

[0085] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = CH2C (O) NH2.

[0086] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 2-R5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2.

[0087] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 3-R5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2.

[0088] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G =

(CH2) 4-R5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2 . [0089] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = (CH2) 5-R5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2.

[0090] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which p = 0. [0091] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which p = 1. [0092] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which p = 1 and the

Carbon atom to which R3 is attached is in the configuration (R).

[0093] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which p = 1 and the Carbon atom to which R3 is attached is in configuration (S). [0094] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which p = 1 and R3

it is -C1-C3 alkyl.

[0095] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which p = 1 and R3 is -CH3. [0096] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which p = 1, R3

it is C1-C3 alkyl and the carbon atom to which R3 is attached is in the configuration (R).

[0097] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which p = 1, R3 is -CH3, and the carbon atom to which R3 is attached is in the configuration (R ). [0098] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which p = 1, R3

it is -C1-C3 alkyl, and the carbon atom to which R3 is attached is in the configuration (S).

[0099] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which p = 1, and R3 is -CH3, and the carbon atom to which R3 is attached is in the configuration ( S). [0100] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which Ar4 is

phenyl. [0101] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which m = 0. [0102] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which m = 1. [0103] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which m = 0, and p

= 0 [0104] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which m = 1 and p =

0.

[0105] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which m = 0, and q = 0.

[0106] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which m = 1 and in which Ar4 is phenyl.

[0107] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which m = 0, p = 0 and in which Ar4 is phenyl.

[0108] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which m = 1, p = 0 and in which Ar4 is phenyl.

[0109] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R2 is -Br, -Cl, -I, or -F.

[0110] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R2 is O (C1-C3 alkyl).

[0111] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R2 is

-C1-C3 alkyl. [0112] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R2 is -CF3 or -OCF3.

[0113] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R3 is -CF3

or -OCF3. [0114] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R2 is NH (C1-C3 alkyl) or -N (C1-C3 alkyl) 2.

[0115] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R3 is -Br, -

Cl, -I, or -F. [0116] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R3 is O (C1-C3 alkyl).

[0117] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R3 is

C1-C3 alkyl. [0118] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R3 is- NH (C1-C3 alkyl), or -N (C1-C3 alkyl) 2.

[0119] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R1 is H.

[0120] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R1 is C (O) NH2, -C (O) NHOH, -C (O) NH (C1-alkyl) C4), or -C (O) N (C1-C4 alkyl) 2. [0121] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R1 is

C (O) N (CH3) 2.

[0122] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R1 is C (O) N (CH2CH3) 2. [0123] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R 1 is

C (O) NHCH3.

[0124] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R1 is C (O) NH (CH2CH3). [0125] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R 1 is

C (O) OR4.

[0126] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R 1 is - CHO. [0127] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R1 is -CN. [0128] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R 1 is

(C1-C4 alkyl).

[0129] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R1 is -CF3, -CHF2, or -CH2F. [0130] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R 1 is

or

[0131] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R1 is

[0132] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which Ar1 is phenyl.

[0133] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which Ar1 is substituted with one or more R2 groups.

[0134] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which Ar2 is phenyl.

[0135] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which Ar2 is substituted with one or more R2 groups.

[0136] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which Ar1 and Ar2 are phenyl.

[0137] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which Ar4 is substituted with one or more R2 groups.

[0138] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which Ar4 is phenyl.

[0139] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which Ar1, Ar2, and Ar4 are phenyl.

[0140] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, and p = 0.

[0141] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, and q = 0.

[0142] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, and m = 0.

[0143] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, and m = 1.

[0144] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, and Ar1 and Ar2 are phenyl.

[0145] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, p = 0, Ar4 is phenyl.

[0146] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, p = 0, and m = 0.

[0147] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, p = 0, and m = 1.

[0148] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, p = 0, and Ar1 and Ar2 are phenyl.

[0149] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, p = 0, Ar4 is phenyl, and m = 0.

[0150] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, p = 0, Ar4 is phenyl, and m = 1. [0151] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, p =

5 0, Ar4 is phenyl, and Ar1 and Ar2 are phenyl. [0152] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, p = 0, Ar2 is phenyl, m = 0, and Ar1 and Ar2 are phenyl.

[0153] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = H, p = 0, Ar4 is phenyl, m = 1, and Ar1 and Ar2 are phenyl. [0154] Illustrative compounds of 4-oxadiazolyl-piperidine of formula (I) have the following structure:

and pharmaceutically acceptable salts thereof, wherein G and R1 are presented as follows:

Compound Number:

G: R1:

AAA

-H -H

AAB

-CH2C (O) NH2  -H

AAC

-CH2C (O) N (CH3) 2  -H

ADF

-C (O) CH2NHSO2CH3  -H

AAE

- (CH2) 2C (O) NH2  -H

AAF

- (CH2) 2C (O) N (CH3) 2  -H

AAG

-C (O) (CH2) 2NHSO2CH3  -H

AAH

-CH2CO2CH3  -H

AAI

-CH2CO2CH2CH3  -H

AAJ

- (CH2) 2CO2CH3  -H

AAK

- (CH2) 2CO2CH2CH3  -H

AAL

- (CH2) 3CO2CH3  -H

AAM

- (CH2) 3CO2CH2CH3  -H

AAN

- (CH2) 4CO2CH3  -H

AAO

- (CH2) 4CO2CH2CH3  -H

AAP

-CH2SO2NH2  -H

AAQ

-CH2SO2N (CH3) 2  -H

AAR

- (CH2) 2NHSO2H -H

AAS

- (CH2) 2NHSO2CH3  -H

AAT

- H -C (O) NH2

AAU

-CH2C (O) NH2  -C (O) NH2

AAV

-CH2C (O) N (CH3) 2  -C (O) NH2

AAW

-CH2NHSO2CH -C (O) NH2

AAX

- (CH2) 2C (O) NH2  -C (O) NH2

Aay

- (CH2) 2C (O) N (CH3) 2  -C (O) NH2

AAZ

- (CH2) 2NHSO2CH3  -C (O) NH2

ABA

-CH2CO2CH3  -C (O) NH2

ABB

-CH2CO2CH2CH3  -C (O) NH2

ABC

- (CH2) 2CO2CH3  -C (O) NH2

ABD

- (CH2) 2CO2CH2CH3  -C (O) NH2

ABE

- (CH2) 3CO2CH3  -C (O) NH2

Compound Number:

G: R1:

ABF

- (CH2) 3CO2CH2CH3  -C (O) NH2

ABG

- (CH2) 4CO2CH3  -C (O) NH2

ABH

- (CH2) 4CO2CH2CH3  -C (O) NH2

ABI

-CH2SO2NH2  -C (O) NH2

ABJ

-CH2SO2N (CH3) 2  -C (O) NH2

ABK

- (CH2) 2NHSO2H -C (O) NH2

ABL

- (CH2) 2NHSO2CH3  -C (O) NH2

ABM

- H -CO2CH3

ABN

-CH2C (O) NH2  -CO2CH3

ABO

-CH2C (O) N (CH3) 2  -CO2CH3

ABP

-C (O) CH2NHSO2CH3  -CO2CH3

ABQ

- (CH2) 2C (O) NH2  -CO2CH3

APR

- (CH2) 2C (O) N (CH3) 2  -CO2CH3

ABS

-C (O) (CH2) 2NHSO2CH3  -CO2CH3

ABT

-CH2CO2CH3  -CO2CH3

ABU

-CH2CO2CH2CH3  -CO2CH3

ABV

- (CH2) 2CO2CH3  -CO2CH3

ABW

- (CH2) 2CO2CH2CH3  -CO2CH3

ABX

- (CH2) 3CO2CH3  -CO2CH3

BBY

- (CH2) 3CO2CH2CH3  -CO2CH3

ABZ

- (CH2) 4CO2CH3  -CO2CH3

HERE

- (CH2) 4CO2CH2CH3  -CO2CH3

ACB

-CH2SO2NH2  -CO2CH3

ACC

-CH2SO2N (CH3) 2  -CO2CH3

ACD

- (CH2) 2NHSO2H -CO2CH3

ACE

- (CH2) 2NHSO2CH3  -CO2CH3

ACF

- H -CHO

ACG

-CH2C (O) NH2  -CHO

ACH

-CH2C (O) N (CH3) 2  -CHO

Acl

-C (O) CH2NHSO2CH3  -CHO

ACJ

- (CH2) 2C (O) NH2  -CHO

ACK

- (CH2) 2C (O) N (CH3) 2  -CHO

ACL

-C (O) (CH2) 2NHSO2CH3  -CHO

ACM

-CH2CO2CH3  -CHO

ACN

-CH2CO2CH2CH3  -CHO

ACO

- (CH2) 2CO2CH3  -CHO

ACP

- (CH2) 2CO2CH2CH3  -CHO

ACQ

- (CH2) 3CO2CH3  -CHO

ACR

- (CH2) 3CO2CH2CH3  -CHO

ACS

- (CH2) 4CO2CH3  -CHO

ACT

- (CH2) 4CO2CH2CH3  -CHO

ACU

-CH2SO2NH2  -CHO

ACV

-CH2SO2N (CH3) 2  -CHO

ACW

- (CH2) 2NHSO2H -CHO

ACX

- (CH2) 2NHSO2CH3  -CHO

ACY

- H -CN

ACZ

-CH2C (O) NH2  -CN

ADA

-CH2C (O) N (CH3) 2  -CN

ADB

-C (O) CH2NHSO2CH3  -CN

ADC

- (CH2) 2C (O) NH2  -CN

ADD

- (CH2) 2C (O) N (CH3) 2  -CN

ADE

-C (O) (CH2) 2NHSO2CH3  -CN

ADF

-CH2CO2CH3  -CN

ADG

-CH2CO2CH2CH3  -CN

ADH

- (CH2) 2CO2CH3  -CN

ADI

- (CH2) 2CO2CH2CH3  -CN

ADJ

- (CH2) 3CO2CH3  -CN

ADK

- (CH2) 3CO2CH2CH3  -CN

ADL

- (CH2) 4CO2CH3  -CN

ADM

- (CH2) 4CO2CH2CH3  -CN

Compound Number:

G: R1:

AND

-CH2SO2NH2  -CN

ADO

-CH2SO2N (CH3) 2  -CN

ADP

- (CH2) 2NHSO2H -CN

ADQ

- (CH2) 2NHSO2CH3  -CN

ADR

-H -CH3

ADS

CH2C (O) NH2  -CH3

ADT

-CH2C (O) N (CH3) 2  -CH3

ADU

-C (O) CH2NHSO2CH3  -CH3

ADV

- (CH2) 2C (O) NH2  -CH3

ADW

- (CH2) 2C (O) N (CH3) 2  -CH3

ADX

-C (O) (CH2) 2NHSO2CH3  -CH3

ADY

-CH2CO2CH3  -CH3

ADZ

-CH2CO2CH2C -CH3

SAA

- (CH2) 2CO2CH3  -CH3

AEB

- (CH2) 2CO2CH2CH3  -CH3

BCE

- (CH2) 3CO2CH3  -CH3

AED

- (CH2) 3CO2CH2CH3  -CH3

EEA

- (CH2) 4CO2CH3  -CH3

AEF

- (CH2) 4CO2CH2CH3  -CH3

AEG

-CH2SO2NH2  -CH3

AEH

-CH2SO2N (CH3) 2  -CH3

AEI

- (CH2) 2NHSO2H -CH3

AEJ

- (CH2) 2NHSO2CH3  -CH3

AEK

- H -C (O) NH (CH3)

TO THE

-CH2C (O) NH2  -C (O) NH (CH3)

AEM

-CH2C (O) N (CH3) 2  -C (O) NH (CH3)

AEN

-C (O) CH2NHSO2CH3  -C (O) NH (CH3)

AEO

- (CH2) 2C (O) NH2  -C (O) NH (CH3)

AEP

- (CH2) 2C (O) N (CH3) 2  -C (O) NH (CH3)

AEQ

-C (O) (CH2) 2NHSO2CH3  -C (O) NH (CH3)

AER

-CH2CO2CH3  -C (O) NH (CH3)

AES

-CH2CO2CH2CH3  -C (O) NH (CH3)

AET

- (CH2) 2CO2CH3  -C (O) NH (CH3)

AEU

- (CH2) 2CO2CH2CH3  -C (O) NH (CH3)

AEV

- (CH2) 3CO2CH3  -C (O) NH (CH3)

AEW

- (CH2) 3CO2CH2CH3  -C (O) NH (CH3)

AEX

- (CH2) 4CO2CH3  -C (O) NH (CH3)

AEY

- (CH2) 4CO2CH2CH3  -C (O) NH (CH3)

AEZ

-CH2SO2NH2  -C (O) NH (CH3)

AFA

-CH2SO2N (CH3) 2  -C (O) NH (CH3)

AFB

- (CH2) 2NHSO2H -C (O) NH (CH3)

AFC

- (CH2) 2NHSO2CH3  -C (O) NH (CH3)

AFD

- H -C (O) N (CH3) 2

AFE

-CH2C (O) NH2  -C (O) N (CH3) 2

AFF

-CH2C (O) N (CH3) 2  -C (O) N (CH3) 2

AFG

-C (O) CH2NHSO2CH3  -C (O) N (CH3) 2

AFH

- (CH2) 2C (O) NH2  -C (O) N (CH3) 2

AFI

- (CH2) 2C (O) N (CH3) 2  -C (O) N (CH3) 2

AFJ

-C (O) (CH2) 2NHSO2CH3  -C (O) N (CH3) 2

AFK

-CH2CO2CH3  -C (O) N (CH3) 2

AFL

-CH2CO2CH2CH3  -C (O) N (CH3) 2

AFM

- (CH2) 2CO2CH3  -C (O) N (CH3) 2

AFN

- (CH2) 2CO2CH2CH3  -C (O) N (CH3) 2

AFO

- (CH2) 3CO2CH3  -C (O) N (CH3) 2

AFP

- (CH2) 3CO2CH2CH3  -C (O) N (CH3) 2

AFQ

- (CH2) 4CO2CH3  -C (O) N (CH3) 2

AFR

- (CH2) 4CO2CH2CH3  -C (O) N (CH3) 2

AFS

-CH2SO2NH2  -C (O) N (CH3) 2

AFT

-CH2SO2N (CH3) 2  -C (O) N (CH3) 2

AFU

- (CH2) 2NHSO2H -C (O) N (CH3) 2

Compound Number:

G: R1:

AFV

- (CH2) 2NHSO2CH3  -C (O) N (CH3) 2

AFW

- H

AFX

-CH2C (O) NH2

AFY

-CH2C (O) N (CH3) 2

AFZ

-C (O) CH2NHSO2CH

AGA

- (CH2) 2C (O) NH2

AGB

- (CH2) 2C (O) N (CH3) 2

AGC

-C (O) (CH2) 2NHSO2CH3

AGD

-CH2CO2CH3

AGE

-CH2CO2CH2CH3

AGF

- (CH2) 2CO2CH3

AGG

- (CH2) 2CO2CH2CH3

AGH

- (CH2) 3CO2CH3

Compound Number:

G: R1:

AGI

- (CH2) 3CO2CH2CH3

AGJ

- (CH2) 4CO2CH3

AGK

- (CH2) 4CO2CH2CH3

AGL

-CH2SO2NH2

AGM

-CH2SO2N (CH3) 2

AGN

- (CH2) 2NHSO2H

AUG

- (CH2) 2NHSO2CH3

AGP

-H

AGQ

-CH2C (O) NH2

AGR

-CH2C (O) N (CH3) 2

AGS

-C (O) CH2NHSO2CH3

AGT

- (CH2) 2C (O) NH2

Compound Number:

G: R1:

AGU

- (CH2) 2C (O) N (CH3) 2

AGV

-C (O) (CH2) 2NHSO2CH3

AGW

-CH2CO2CH3

AGX

-CH2CO2CH2CH)

AGY

- (CH2) 2CO2CH3

AGZ

- (CH2) 2CO2CH2CH3

Aha

- (CH2) 3CO2CH3

AHB

- (CH2) 3CO2CH2CH3

AHC

- (CH2) 4CO2CH3

AHD

- (CH2) 4CO2CH2CH3

AHE

-CH2SO2NH2

AHF

-CH2SO2N (CH3) 2

Compound Number:

G: R1:

AHG

- (CH2) 2NHSO2H

AHH

- (CH2) 2NHSO2CH3

THERE

-H

AHJ

-CH2C (O) NH2

AHK

-CH2C (O) N (CH3) 2

AHL

-C (O) CH2NHSO2CH3

AHM

- (CH2) 2C (O) NH2

AHN

- (CH2) 2C (O) N (CH3) 2

AH OR

-C (O) (CH2) 2NHSO2CH3

AHP

-CH2CO2CH3

AH Q

-CH2CO2CH2CH3

AHR

- (CH2) 2CO2CH3

Compound Number:

G: R1:

AHS

- (CH2) 2CO2CH2CH3

AHT

- (CH2) 3CO2CH3

AHU

- (CH2) 3CO2CH2CH3

AHV

- (CH2) 4CO2CH3

AHW

- (CH2) 4CO2CH2CH3

AHX

-CH2SO2NH2

AHY

-CH2SO2N (CH3) 2

AHZ

- (CH2) 2NHSO2H

AIA

- (CH2) 2NHSO2CH3

AIR

-H

AIC

-CH2C (O) NH2

AID

-CH2C (O) N (CH3) 2

Compound Number:

G: R1:

IEA

-C (O) CH2NHSO2CH3

IDA

- (CH2) 2C (O) NH2

AIG

- (CH2) 2C (O) N (CH3) 2

AIH

-C (O) (CH2) 2NHSO2CH3

AII

-CH2CO2CH3

AIJ

-CH2CO2CH2CH3

AIK

- (CH2) 2CO2CH3

AIL

- (CH2) 2CO2CH2CH3

AIM

- (CH2) 3CO2CH3

Ain

- (CH2) 3CO2CH2CH3

AIO

- (CH2) 4CO2CH3

AIP

- (CH2) 4CO2CH2CH3

Compound Number:

G: R1:

AIQ

-CH2SO2NH2

AIR

-CH2SO2N (CH3) 2

AIS

- (CH2) 2NHSO2H

AIT

- (CH2) 2NHSO2CH3

AIU

-H

AIV

-CH2C (O) NH2

AIW

-CH2C (O) N (CH3) 2

AIX

-C (O) CH2NHSO2CH3

AIY

- (CH2) 2C (O) NH2

AIZ

- (CH2) 2C (O) N (CH3) 2

AHA

-C (O) (CH2) 2NHSO2CH3

AJB

-CH2CO2CH3

Compound Number:

G: R1:

AJC

-CH2CO2CH2CH3

AJD

- (CH2) 2CO2CH3

AJE

- (CH2) 2CO2CH2CH3

AJF

- (CH2) 3CO2CH3

AJG

- (CH2) 3CO2CH2CH3

Akh

- (CH2) 4CO2CH3

CHILI PEPPER

- (CH2) 4CO2CH2CH3

AJJ

-CH2SO2NH2

AJK

-CH2SO2N (CH3) 2

AJL

- (CH2) 2NHSO2H

AJM

- (CH2) 2NHSO2CH3

AJN

- (CH2) 3NHSO2H -H

GARLIC

- (CH2) 3NHSO2H -C (O) NH2

AJP

- (CH2) 3NHSO2H -CO2CH3

AJQ

- (CH2) 3NHSO2H -CHO

AJR

- (CH2) 3NHSO2H -CN

AJS

- (CH2) 3NHSO2H -CH3

Compound Number:

G: R1:

AJT

- (CH2) 3NHSO2H -C (O) NHCH3

AJU

- (CH2) 3NHSO2H -C (O) N (CH3) 2

AJV

- (CH2) 3NHSO2H

AJW

- (CH2) 3NHSO2H

AJX

- (CH2) 3NHSO2H

AJY

- (CH2) 3NHSO2H

[0155] The present invention further encompasses compounds having the formula (II):

15 and pharmaceutically acceptable salts thereof, wherein Ar3, Ar4, R1-R3, G, n, m, p and q are as defined above.

[0156] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G is H.

[0157] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = C (O) (CH2) nC (O) OR4.

[0158] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = 25 (C1-C5 alkylene) R5.

[0159] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = -CH2-R5

.

[0160] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = CH2) 2-R5

.

[0161] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (CH2) 3-R5.

[0162] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (CH2) 4-R5.

[0163] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = 40 (CH2) 5-R5.

[0164] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = C (O) (CH2) nC (O) OR4 and R4 = H.

[0165] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = C (O) (CH2) nC (O) OR4 and R4 = alkyl -C1-C10.

[0166] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = C (O) (CH2) nC (O) OR4 and R4 = -CH2O (C1-C4 alkyl) .

[0167] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = C (O) (CH2) nC (O) OR4 and R4 = - CH2NH (C1-C4 alkyl) or -CH2N (C1-C4 alkyl) 2.

[0168] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (C1-C5 alkylene) COOR4.

[0169] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = -CH2-COOR4.

[0170] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = -CH2COOCH2CH3.

[0171] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (CH2) 2-COOR4.

[0172] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (CH2) 3-COOR4.

[0173] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (CH2) 4-COOR4.

[0174] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (CB2) 5-COOR4.

[0175] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = -C (O) (CH2) nR5 and R5 = - NHSO2R4.

[0176] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = C (O) (CH2) nR5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2.

[0177] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = -C (O) (CH2) nR5 and R5 = -SO2NH2, -SO2NH (C1-C4 alkyl) , or -SO2N (C1-C4 alkyl) 2.

[0178] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = -C (O) (CH2) nR5 and R5 = -NHSO2H.

[0179] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = -C (O) (CH2) nR5.

[0180] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (C1-C5 alkylene) R5.

[0181] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (C1-C5 alkylene) R5 and R5 = -C (O) NH2, -C (O) NHOH , -C (O) NH (C1-C4 alkyl), or C- (O) N (C1-C4 alkyl) 2.

[0182] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = -CH2R5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O ) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2.

[0183] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = -CH2C (O) N (CH3) 2.

[0184] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which G = CH2C (O) NH2.

[0185] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G =

(CH2) 2-R5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2 . [0186] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (CH2) 3-R5 and R5 = -C (O) NH5, -C (O) NHOH, -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2.

[0187] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G =

(CH2) 4-R5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2 . [0188] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = (CH2) 5-R5 and R5 = -C (O) NH2, -C (O) NHOH, -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) 2 .

[0189] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which p = 0. [0190] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which p = 1. [0191] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which p = 1 and the

Carbon atom to which R3 is attached is in the configuration (R).

[0192] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which p = 1 and the Carbon atom to which R3 is attached is in configuration (S). [0193] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which p = 1 and R3

it is -C1-C3 alkyl.

[0194] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which p = 1 and R3 is -CH3. [0195] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which p = 1, R3

it is C1-C3 alkyl and the carbon atom to which R3 is attached is in the configuration (R).

[0196] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which p = 1, R3 is -CH3, and the carbon atom to which R3 is attached is in the configuration (R ). [0197] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which p = 1, R3

it is -C1-C3 alkyl, and the carbon atom to which R3 is attached is in the configuration (S).

[0198] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which p = 1, R3 is -CH3, and the carbon atom to which R3 is attached is in the configuration (S ). [0199] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which Ar4 is

phenyl. [0200] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which m = 0. [0201] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which m = 1. [0202] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which m = 0, and p

= 0

[0203] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which m = 1 and p = 0. [0204] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula ( II) are those in which m = 0 and in

those that Ar4 is phenyl.

[0205] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which m = 1 and Ar4 It is phenyl. [0206] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which m = 0, p =

0 and Ar4 is phenyl. [0207] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which m = 1, p = 0 and Ar4 is phenyl.

[0208] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R2 is -Br, -

Cl, -I, or -F. [0209] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R2 is - O (-C1-C3 alkyl).

[0210] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R2 is -

-C1-C3 alkyl. [0211] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R2 is -CF3 or -OCF3.

[0212] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R3 is -CF3

or -OCF3. [0213] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R3 is NH (C1-C3 alkyl) or -N (C1-C3 alkyl) 2.

[0214] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R3 is -Br, -

Cl, -I, or -F. [0215] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R3 is O (C1-C3 alkyl).

[0216] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R 3 is

C1-C3 alkyl. [0217] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R 3 is NH (C1-C3 alkyl), or -N (C1-C3 alkyl) 2.

[0218] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R1 is H.

[0219] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R1 is C (O) NH2, -C (O) NHOH, -C (O) NH (C1-alkyl) C4), or -C (O) N (C1-C4 alkyl) 2. [0220] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R 1 is

C (O) N (CH3) 2.

[0221] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R1 is C (O) N (CH2CH3) 2. [0222] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R 1 is

C (O) NHCH3.

[0223] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R1 is C (O) NHCH2CH3. [0224] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R 1 is -

COOR4.

[0225] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R 1 is - CHO. [0226] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R1 is -CN. [0227] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (I) are those in which R1 is -CF3,

-

CHF2, or -CH2F.

[0228] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R 1 is (C 1 -C 4 alkyl). [0229] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R 1 is

[0230] In another embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which R 1 is

[0231] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which Ar3 is phenyl.

[0232] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which Ar3 is substituted with one, two, or three R2 groups.

[0233] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which Ar4 is phenyl.

[0234] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which Ar4 is substituted with one, two, or three R2 groups.

[0235] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, and p = 0.

[0236] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, and Ar4 is phenyl.

[0237] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, and m = 0.

[0238] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, and m = 1.

[0239] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, and Ar3 is phenyl.

[0240] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, p = 0 and Ar4 is phenyl.

[0241] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, p = 0, and m = 0.

[0242] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, p = 0, and m = 1.

[0243] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, p = 0, and Ar3 is phenyl.

[0244] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, p = 0, Ar4 is phenyl, and m = 0.

[0245] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, p = 0, Ar4 is phenyl, and m = 1.

[0246] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, p = 0, Ar4 is phenyl, and Ar3 is phenyl.

[0247] In one embodiment, the 4-oxadiazolyl-piperidine Compounds of formula (II) are those in which G = H, p = 0, Ar4 is phenyl, m = 0, and Ar3 is phenyl.

[0248] Illustrative compounds of 4-oxadiazolyl-piperidine of formula (II) have the following structure:

where G and R1 are presented as follows:

Compound Number:

G: R1:

BAA

-H -H

BAB

-CH2C (O) NH2  -H

BAC

-CH2C (O) N (CH3) 2  -H

BAD

-C (O) CH2NHSO2CH3  -H

BAE

- (CH2) 2C (O) NH2  -H

BAF

- (CH2) 2C (O) N (CH3) 2  -H

Bag

-C (O) (CH2) 2NHSO2CH3  -H

BAH

-CH2CO2CH3  -H

BAI

-CH2CO2CH2CH3  -H

LOW

- (CH2) 2CO2CH3  -H

BAK

- (CH2) 2CO2CH2CH3  -H

BAL

- (CH2) 3CO2CH3  -H

BAM

- (CH2) 3CO2CH2CH3  -H

BAN

- (CH2) 4CO2CH3  -H

BEAM

- (CH2) 4CO2CH2CH3  -H

BAP

-CH2SO2NH2  -H

BAQ

-CH2SO2N (CH3) 2  -H

PUB

- (CH2) 2NHSO2H -H

BAS

- (CH2) 2NHSO2CH3  -H

BAT

- H -C (O) NH2

BAU

-CH2C (O) NH2  -C (O) NH2

BAV

-CH2C (O) N (CH3) 2  -C (O) NH2

BAW

-CH2NHSO2CH3  -C (O) NH2

BAX

- (CH2C (O) NH2  -C (O) NH2

BAY

- (CH2) 2C (O) N (CH3) 2  -C (O) NH2

BAZ

- (CH2) 2NHSO2CH3  -C (O) NH2

BBA

-CH2CO2CH3  -C (O) NH2

BBB

-CH2CO2CH2CH3  -C (O) NH2

BBC

- (CH2) 2CO2CH3  -C (O) NH2

BBD

- (CH2) 2CO2CH2CH3  -C (O) NH2

BBE

- (CH2) 3CO2CH3  -C (O) NH2

BBF

- (CH2) 3CO2CH2CH3  -C (O) NH2

Bbg

- (CH2) 4CO2CH3  -C (O) NH2

Bbh

- (CH2) 4CO2CH2CH3  -C (O) NH2

BBI

-CH2SO2NH2  -C (O) NH2

BBJ

-CH2SO2N (CH3) 2  -C (O) NH2

BBK

- (CH2) 2NHSO2H -C (O) NH2

BBL

= (CH2) 2NHSO2CH3  -C (O) NH2

BBM

- H -CO2CH3

Compound Number:

G: R1:

BBN

-CH2C (O) NH2  -CO2CH3

BBO

-CH2C (O) N (CH3) 2  -CO2CH3

BBP

-C (O) CH2NHSO2CH3  -CO2CH3

BBQ

- (CH2) 2C (O) NH2  -CO2CH3

BBR

- (CH2) 2C (O) N (CH3) 2  -CO2CH3

BBS

-C (O) (CH2) 2NHSO2CH3  -CO2CH3

BBT

-CH2CO2CH3  -CO2CH3

BBU

-CH2CO2CH2CH3  -CO2CH3

BBV

- (CH2) 2CO2CH3  -CO2CH)

Bbw

- (CH2) 2CO2CH2CH3  -CO2CH3

BBX

- (CH2) 3CO2CH3  -CO2CH3

BBY

- (CH2) 3CO2CH2CH3  -CO2CH3

BBZ

- (CH2) 4CO2CH3  -CO2CH3

BCA

- (CH2) 4CO2CH2CH3  -CO2CH3

BCB

-CH2SO2NH2  -CO2CH3

BCC

-CH2SO2N (CH3) 2  -CO2CH3

B C D

- (CH2) 2NHSO2H -CO2CH3

ECB

- (CH2) 2NHSO2CH3  -CO2CH3

BCF

- H -CHO

BCG

-CH2C (O) NH2  -CHO

BCH

-CH2C (O) N (CH3) 2  -CHO

BCI

-C (O) CH2NHSO2CH3  -CHO

BCJ

- (CH2) 2C (O) NH2  -CHO

BCK

- (CH2) 2C (O) N (CH3) 2  -CHO

BCL

-C (O) (CH2) 2NHSO2CH3  -CHO

BCM

-CH2CO2CH3  -CHO

BCN

-CH2CO2CH2CH3  -CHO

BCO

- (CH2) 2CO2CH3  -CHO

BCP

- (CH2) 2CO2CH2CH3  -CHO

BCQ

- (CH2) 3CO2CH3  -CHO

BCR

- (CH2) 3CO2CH2CH3  -CHO

BCS

- (CH2) 4CO2CH3  -CHO

BCT

- (CH2) 4CO2CH2CH3  -CHO

BCU

-CH2SO2NH2  -CHO

BCV

-CH2SO2N (CH3) 2  -CHO

BCW

- (CH2) 2NHSO2H -CHO

BCX

- (CH2) 2NHSO2CH3  -CHO

BCY

- H -CN

BCZ

-CH2C (O) NH2  -CN

BDA

-CH2C (O) N (CH3) 2  -CN

BDB

-C (O) CH2NHSO2CH3  -CN

BDC

- (CH2) 2C (O) NH2  -CN

BDD

- (CH2) 2C (O) N (CH3) 2  -CN

BDE

-C (O) (CH2) 2NHSO2CH3  -CN

BDF

-CH2CO2CH3  -CN

BDG

-CH2CO2CH2CH3  -CN

BDH

- (CH2) 2CO2CH3  -CN

BDI

- (CH2) 2CO2CH2CH3  -CN

BDJ

- (CH2) 3CO2CH3  -CN

BDK

- (CH2) 3CO2CH2CH3  -CN

BDL

- (CH2) 4CO2CH3  -CN

BDM

- (CH2) 4CO2CH2CH3  -CN

BND

-CH2SO2NH2  -CN

BDO

-CH2SO2N (CH3) 2  -CN

BDP

- (CH2) 2NHSO2H -CN

BDQ

- (CH2) 2NHSO2CH3  -CN

BDR

- H -CH3

BDS

-CH2C (O) NH2  -CH3

BDT

-CH2C (O) N (CH3) 2  -CH3

BDU

-C (O) CH2NHSO2CH3  -CH3

Compound Number:

G: R1:

BDV

- (CH2) 2C (O) NH2  -CH3

BDW

- (CH2) 2C (O) N (CH3) 2  -CH3

BDX

-C (O) (CH2) 2NHSO2CH3  -CH3

BDY

-CH2CO2CH3  -CH3

BDZ

-CH2CO2CH2CH3  -CH3

BEA

- (CH2) 2CO2CH3  -CH3

BEB

- (CH2) 2CO2CH2CH3  -CH3

BEC

- (CH2) 3CO2CH3  -CH3

BED

- (CH2) 3CO2CH2CH3  -CH3

BEE

- (CH2) 4CO2CH3  -CH3

BEF

- (CH2) 4CO2CH2CH3  -CH3

BEG

-CH2SO2NH2  -CH3

Beh

-CH2SO2N (CH3) 2  -CH3

EIB

- (CH2) 2NHSO2H -CH3

BEJ

- (CH2) 2NHSO2CH3  -CH3

BEK

- H -C (O) NH (CH3)

BEL

-CH2C (O) NH2  -C (O) NH (CH3)

BEM

-CH2C (O) N (CH3) 2  -C (O) NH (CH3)

BEN

-C (O) CH2NHSO2CH3  -C (O) NH (CH3)

BEO

- (CH2) 2C (O) NH2  -C (O) NH (CH3)

BEP

- (CH2) 2C (O) N (CH3) 2  -C (O) NH (CH3)

BEQ

-C (O) (CH2) 2NHSO2CH3  -C (O) NH (CH3)

BER

-CH2CO2CH3  -C (O) NH (CH3)

BES

-CH2CO2CH2CH3  -C (O) NH (CH3)

BET

- (CH2) 2CO2CH3  -C (O) NH (CH3)

BEU

- (CH2) 2CO2CH2CH3  -C (O) NH (CH3)

BEV

- (CH2) 3CO2CH3  -C (O) NH (CH3)

BEW

- (CH2) 3CO2CH2CH3  -C (O) NH (CH3)

BEX

- (CH2) 4CO2CH3  -C (O) NH (CH3)

BEY

- (CH2) 4CO2CH2CH3  -C (O) NH (CH3)

BEZ

-CH2SO2NH2  -C (O) NH (CH3)

BFA

-CH2SO2N (CH3) 2  -C (O) NH (CH3)

BFB

- (CH2) 2NHSO2H -C (O) NH (CH3)

BFC

- (CH2) 2NHSO2CH3  -C (O) NH (CH3)

BFD

- H -C (O) N (CH3) 2

BFE

-CH2C (O) NH2  -C (O) N (CH3) 2

BFF

-CH2C (O) N (CH3) 2  -C (O) N (CH3) 2

BFG

-C (O) CH2NHSO2CH3  -C (O) N (CH3) 2

BFH

- (CH2) 2C (O) NH2  -C (O) N (CH3) 2

BFI

- (CH2) 2C (O) N (CH3) 2  -C (O) N (CH3) 2

BFJ

-C (O) (CH2) 2NHSO2CH3  -C (O) N (CH3) 2

BFK

-CH2CO2CH3  -C (O) N (CH3) 2

BFL

-CH2CO2CH2CH3  -C (O) N (CH3) 2

BFM

- (CH2) 2CO2CH3  -C (O) N (CH3) 2

BFN

- (CH2) 2CO2CH2CH3  -C (O) N (CH3) 2

BFO

- (CH2) 3CO2CH3  -C (O) N (CH3) 2

BFP

- (CH2) 3CO2CH2CH3  -C (O) N (CH3) 2

BFQ

- (CH2) 4CO2CH3  -C (O) N (CH3) 2

BFR

- (CH2) 4CO2CH2CH3  -C (O) N (CH3) 2

BFS

-CH2SO2NH2  -C (O) N (CH3) 2

BFT

-CH2SO2N (CH3) 2  -C (O) N (CH3) 2

BFU

- (CH2) 2NHSO2H -C (O) N (CH3) 2

BFV

- (CH2) 2NHSO2CH3  -C (O) N (CH3) 2

BFW

- H

Compound Number:

G: R1:

BFX

-CH2C (O) NH2

BFY

-CH2C (O) N (CH3) 2

BFZ

-C (O) CH2NHSO2CH3

BGA

- (CH2) 2C (O) NH2

BGB

- (CH2) 2C (O) N (CH3) 2

BGC

-C (O) (CH2) 2NHSO2CH3

BGD

-CH2CO2CH3

BGE

-CH2CO2CH2CH3

BGF

- (CH2) 2CO2CH3

BGG

- (CH2) 2CO2CH2CH3

BGH

- (CH2) 3CO2CH3

BGI

- (CH2) 3CO2CH2CH3

Compound Number:

G: R1:

BGJ

- (CH2) 4CO2CH3

BGK

- (CH2) 4CO2CH2CH3

BGL

-CH2SO2NH2

BGM

-CH2SO2N (CH3) 2

BGN

- (CH2) 2NHSO2H

BGO

- (CH2) 2NHSO2CH3

BGP

-H

BGQ

-CH2C (O) NH2

BGR

-CN2C (O) N (CH3) 2

BGS

-C (O) CH2NHSO2CH3

BGT

- (CH2) 2C (O) NH2

BGU

- (CH2) 2C (O) N (CH3) 2

Compound Number:

G: R1:

BGV

-C (O) (CH2) 2NHSO2CH3

BGW

-CH2CO2CH3

BGX

-CH2CO2CH2CH3

BGY

- (CH2) 2CO2CH3

BGZ

- (CH2) 2CO2CH2CH3

BHA

- (CH2) 3CO2CH3

BHB

- (CH2) 3CO2CH2CH3

BHC

- (CH2) 4CO2CH3

BHD

- (CH2) 4CO2CH2CH3

BHE

-CH2SO2NH2

BHF

-CH2SO2N (CH3) 2

BHG

- (CH2) 2NHSO2H

Compound Number:

G: R1:

Bhh

- (CH2) 2NHSO2CH3

BHI

-H

BHJ

-CH2C (O) NH2

Bhk

-CH2C (O) N (CH3) 2

BHL

-C (O) CH2NHSO2CH3

BHM

- (CH2) 2C (O) NH2

BHN

- (CH2) 2C (O) N (CH3) 2

BHO

-C (O) (CH2) 2NHSO2CH3

BHP

-CH2CO2CH3

BHQ

-CH2CO2CH2CH3

BHR

- (CH2) 2CO2CH3

BHS

- (CH2) 2CO2CH2CH3

Compound Number:

G: R1:

B HT

- (CH2) 3CO2CH3

Bhu

- (CH2) 3CO2CH2CH3

BHV

- (CH2) 4CO2CH3

BHW

- (CH2) 4CO2CH2CH3

Bhx

-CH2SO2NH2

BHY

-CH2SO2N (CH3) 2

Bhz

- (CH2) 2NHSO2H

BIA

- (CH2) 2NHSO2CH3

BIB

-H

BIC

-CH2C (O) NH2

IDB

-CH2C (O) N (CH3) 2

BIE

-C (O) CH2NHSO2CH3

Compound Number:

G: R1:

BIF

- (CH2) 2C (O) NH2

BIG

- (CH2) 2C (O) N (CH3) 2

BIH

-C (O) (CH2) 2NHSO2CH3

BII

-CH2CO2CH3

BIJ

-CH2CO2CH2CH3

BIK

- (CH2) 2CO2CH3

BIL

- (CH2) 2CO2CH2CH3

BIM

- (CH2) 3CO2CH3

BIN

- (CH2) 3CO2CH2CH3

BIO

- (CH2) 4CO2CH3

BEEP

- (CH2) 4CO2CH2CH3

BIQ

-CH2SO2NH2

Compound Number:

G: R1:

BIR

-CH2SO2N (CH3) 2

BIS

- (CH2) 2NHSO2H

BIT

- (CH2) 2NHSO2CH3

BIU

-H

BIV

-CH2C (O) NH2

BIW

-CH2C (O) N (CH3) 2

BIX

-C (O) CH2NHSO2CH3

BIY

- (CH2) 2C (O) NH2

BIZ

- (CH2) 2C (O) N (CH3) 2

BJA

-C (O) (CH2) 2NHSO2CH3

BJB

-CH2CO2CH3

BJC

-CH2CO2CH2CH3

Compound Number:

G: R1:

BJD

- (CH2) 2CO2CH3

BJE

- (CH2) 2CO2CH2CH3

BJF

- (CH2) 3CO2CH3

BJG

- (CH2) 3CO2CH2CH3

BJH

- (CH2) 4CO2CH3

BJI

- (CH2) 4CO2CH2CH3

BJJ

-CH2SO2NH2

BJK

-CH2SO2N (CH3) 2

BJL

- (CH2) 2NHSO2H

BJM

- (CH2) 2NHSO2CH3

BJN

- (CH2) 3NHSO2H -H

BJO

- (CH2) 3NHSO2H -C (O) NH2

BJP

- (CH2) 3NHSO2H -CO2CH3

BJQ

- (CH2) 3NHSO2H -CHO

BJR

- (CH2) 3NHSO2H -CN

BJS

- (CH2) 3NHSO2H -CH3

BJT

- (CH2) 3NHSO2H -C (O) NHCH3

BJU

- (CH2) 3NHSO2H -C (O) N (CH3) 2

Compound Number:

G: R1:

BJV

- (CH2) 3NHSO2H

BJW

- (CH2) 3NHSO2H

BJX

- (CH2) 3NHSO2H

BJY

- (CH2) 3NHSO2H

4.3 Methods for performing the 4-oxadiazolyl-piperidine Compounds

[0249] The 4-oxadiazolyl-piperidine Compounds of the present invention can be performed using conventional organic synthesis as well as by the following illustrative methods.

4.3.1 Synthesis of compounds of structure 3

[0250] Scheme 1 represents methods for performing useful intermediates in the synthesis of Compounds of 4–

Oxadiazolyl-piperidine of formula I and formula II, wherein R1 is -C (O) NZ1Z2, where Z1 and Z2 are each independently a group - (C1-C4 alkyl) or Z1 and Z2 and the atom of Nitrogen to which they are attached are considered together to form N- (4-R4) -N'-1-piperazinyl, aziridyl, azetidyl, pyrrolidyl, piperidyl, homopiperidyl, pyrrolyl

or morpholinyl.

[0251] Bromoacids 1 are converted to bromoacid chlorides 2 using thionyl chloride (J. S. Pizey, Synthetic Reactions 2: 65 (1974)), or, as depicted, using oxalyl chloride. Bromoacid chlorides 2 are reacted with Z1Z2NH, optionally in the presence of a base such as Na2CO3, to provide reactive intermediates 3.

20 Scheme 1

4.3.2 Synthesis of Structure Compounds 10

[0252] Scheme 2 represents methods for performing intermediates useful in the synthesis of 4-oxadiazolylpiperidine Compounds of formula I and formula II, in which G is, for example, -CH2C (O) (CH2) nCH3 and where n , p, R3 and Ar4 are as defined above.

[0253] Nitriles 4 are added to a mixture of hydroxylamine hydrochloride and potassium carbonate. The resulting suspension is stirred at room temperature and then at reflux temperature, to provide the amidoxime product 5. The amidoximes 5 are reacted with malonyl chloride derivatives 6 to provide the product N-benzyl-piperidinyl compounds 7. The N-benzyl-piperidinyloxadiazoles 7 are heated in DMF in the presence of molecular sieves to provide the N-benzyl-oxadiazolyl-piperidine 8 compounds, which are reacted with 1-chloroethyl chloroformate 9 to remove the benzyl fraction and provide oxadiazolyl piperidines 10.

Scheme 2

4.3.3 Synthesis of compounds of structure 12

[0254] Scheme 3 represents methods to be used in the synthesis of 4-oxadiazolyl-piperidine Compounds of formula I and formula II, in which R1 is, for example, -C (O) NZ1Z2, where Z1 and Z2 are each independently a group - (C1-C4 alkyl) or Z1 and Z2 and the nitrogen atom to which they are attached are taken together to form N- (4R4) -N'-1-piperazinyl, aziridyl, azetidyl, pyrrolidyl, piperidyl , homopiperidyl, pyrrolyl or morpholinyl; and in which G is, for example, -CH2C (O) (CH2) nCH3; where -W- is –C (Ar1) (Ar2) - or –C (H) (Ar3) -; and n, m, p, Ar1, Ar2, Ar3, Ar4, and R3 are as defined above.

[0255] Reactive intermediates 3 and oxadiazolylpiperidines 10 are combined and stirred, initially at 0 ° C, and then at room temperature to provide 4-oxadiazolyl-piperidine 11 compounds. The 4-oxadiazolylpiperidine 11 compounds can be dissolved in ammonia in methanol ( for example, 7N, Aldrich) and can be stirred at reflux temperature to provide the corresponding amides 12.

Scheme 3

NH3 / Methanol

4.3.4 Synthesis of Structure Compounds 14

[0256] Scheme 4 represents methods to be used in the synthesis of 4-oxadiazolyl-piperidine Compounds of formula I and formula II, in which R1 is -CO2R4 and G is, for example, -CH2C (O) (CH2 ) nCH3; where -W- is –C (Ar1) (Ar2) or -C (H) (Ar3) -; and n, m, p, Ar1, Ar2, Ar3, Ar4 and R3 are as defined above.

[0257] Bromoacid Chlorides 2 (Scheme 1) are reacted with R4OH, optionally in the presence of a base such as pyridine, 4-dimethylaminopyridine, triethylamine or Hunig base, to provide bromoesters 13. Bromoesters 13 are reacted with oxadiazolylpiperidines 10 (Scheme 2) to provide 4-oxadiazolylpiperidines 14.

Scheme 4

4.3.5 Synthesis of Structure Compounds 4

[0258] In certain embodiments, compounds according to structure 4 are prepared according to Scheme 5 (for example, those in which p is 0), which can be used in the synthesis of 4-oxadiazolyl-piperidine Compounds of the invention.

[0259] Commercially available benzyl compounds (Aldrich), where X is -Cl or -Br, are reacted with bis (2-chloroethyl) amine 26 (Aldrich) in DMF in the presence of triethylamine at a temperature within the range of room temperature at 80 ° C, to provide the benzyl protected amine 27.

[0260] Substituted acetonitrile 28, dissolved in THF, is first treated with NaH at room temperature and then reacted with benzyl protected amine 27 at reflux temperature in THF, to provide nitrile 4, which is it can be used, for example, in the synthesis represented in Scheme 2 above.

Scheme 5

[0261] Each structure represented herein is intended to cover all stereoisomers and tautomers thereof, it being understood that each of them is included in the present invention, whether it has been disclosed or

not specifically, and whether or not it represents the stereoisomer or tautomer illustrated herein an excess stereoisomer or tautomer with respect to any other stereoisomer or tautomer thereof. Accordingly, the invention also encompasses 4-oxadiazolyl-piperidine Compounds and their uses as described herein in the form of their individual stereoisomers or tautomers. Additionally, one or more hydrogens, carbons or other atoms of a 4-oxadiazolyl-piperidine Compound can be substituted by an isotope of hydrogen, carbon or other atoms, respectively. Such compounds, which includes the present invention, are useful as research and diagnostic tools in pharmacokinetic studies of metabolism and in binding assays.

4.4 Therapeutic uses of the 4-oxadiazolyl-piperidine Compounds

[0262] According to the invention, the 4-oxadiazolyl-piperidine Compounds are administered to an animal, in one of the embodiments a mammal, in another of the embodiments a human, for use in the treatment or prevention of pain. 4-Oxadiazolyl-piperidine Compounds can be used to treat or prevent acute or chronic pain. For example, the 4-oxadiazolyl-piperidine Compounds can be used, although without imitations, to treat or prevent cancer pain, central pain, labor pain, myocardial infarction pain, pancreatic pain, pain colic, postoperative pain, headache, muscle pain, and pain associated with intensive care.

[0263] Compounds of 4-oxadiazolyl-piperidine can also be used to inhibit, prevent, or treat pain associated with inflammation or inflammatory disease in an animal. The pain to be inhibited, treated or prevented may be associated with an inflammation associated with an inflammatory disease, which may appear when there is an inflammation of the body tissue, and which may be a local inflammatory response and / or a systemic inflammation. For example, the 4-oxadiazolyl-piperidine Compounds can be used to inhibit, treat, or prevent pain associated with inflammatory diseases including, but not limited to: rejection in organ transplantation; reoxygenation injuries resulting from organ transplantation (see J. Mol. Cell Cardiol. 31: 297 303 (1999), by Grupp et al.) including, but not limited to, transplantation of the heart, lungs, liver, or kidneys; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with an increase in bone resorption; inflammatory bowel diseases, such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory diseases of the lungs, such as asthma, adult respiratory distress syndrome, and chronic obstructive airways disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory gum diseases, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and nephrosis; inflammatory skin diseases, including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, neurodegeneration associated with AIDS and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and viral or autoimmune encephalitis; autoimmune diseases, including Type I and Type II diabetes mellitus; diabetic complications, including, but not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy, foot gangrene, atherosclerotic coronary artery disease, peripheral arterial disease , non-ketosic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, and a complication in the skin or mucous membrane (such as an infection, tibial macules, a candidiasic infection or a lipoid diabeticorum necrobiosis); immunocomplex vasculitis, systemic lupus erythematosus (SLE); inflammatory diseases of the heart, such as cardiomyopathy, ischemic heart disease, hypercholesterolemia, and arteriosclerosis; as well as various other diseases that may have significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. The 4-oxadiazolyl-piperidine Compounds can also be used to inhibit, treat, or prevent pain associated with an inflammatory disease that, for example, may be a systemic inflammation of the body, exemplified by a gram-positive or gram-negative shock. , a hemorrhagic or anaphylactic shock, or a shock induced by cancer chemotherapy in response to proinflammatory cytokines, for example, a shock associated with proinflammatory cytokines. Such shock can be induced, for example, by a chemotherapeutic agent that is administered as a treatment for cancer.

[0264] In another embodiment, the 4-oxadiazolyl-piperidine Compounds are administered to an animal, in one of the embodiments a mammal, in another of the embodiments a human, for use in the treatment or prevention of diarrhea. 4-Oxadiazolyl-piperidine Compounds can be used to treat or prevent acute or chronic diarrhea. For example, 4-Oxadiazolyl-piperidine Compounds can be used, but not limited to, to treat or prevent acute diarrhea caused by a virus, such as, but not limited to, Norwalk virus, a Norwalk-type virus , Rotavirus, and Cytomegalovirus; protozoa, such as, but not limited to, Girardia lamlia, Cryptosporidium and Entamoeba histolytica; and bacteria, including, but not limited to, Stapylococcus aureus, Bacillus cereus, Clostridium perfringens, Enterotoxigenic E. coli, Vibrio cholera, E. coli O157: Enterohemorrhagic H5, Vibrio parahaemolyticus, Clostridium difficile, Campylobacter jejuni, Salty Enterovasive coli, Aeromonas, Plesiomonas, Yersinia enterocolitica, Chlamydia, Nisseria gonorrhoeae, and Listeria monocytogenes. For example, the 4-oxadiazolyl-piperidine Compounds can be used to treat or prevent chronic diarrhea classified as one that includes, but is not limited to, osmotic diarrhea, secretory diarrhea, or the result of an inflammatory condition, a syndrome of malabsorption, a mobility disorder, and a chronic infection.

[0265] The present inventor believes that, unlike traditional opioid agonists and non-steroidal anti-inflammatory agents, the 4-oxadiazolyl-piperidine Compounds do not significantly cross the blood brain barrier. Therefore, administration of an effective amount of a 4-oxadiazolyl-piperidine Compound to an animal should result in fewer side effects, including, for example, respiratory depression, unwanted euphoria, sedation, increased tolerance to drugs, and increased drug dependence, which may be derived from the administration of opioid agonists or traditional non-steroidal anti-inflammatory agents. In one of the embodiments, the administration of an effective amount of a 4-oxadiazolyl-piperidine Compound to an animal does not result in any of the aforementioned side effects. For this reason, in certain embodiments, the present uses encompass the treatment or prevention of pain, while reducing or eliminating one or more of the aforementioned side effects.

[0266] Without entering into theoretical discussions, it is believed that the 4-oxadiazolyl-piperidine Compounds are agonists of an opioid receptor and, therefore, are capable of stimulating it. In one embodiment, the opioid receptor is a receptor 1. In another embodiment, the opioid receptor is an ORL-1 receptor. In a further embodiment, the opioid receptor is a receptor 8.

[0267] The invention also relates to the use in the preparation of a medicament for stimulating the function of opioid receptors in a cell, which comprises contacting a cell capable of expressing an opioid receptor with an effective amount of a Compound of 4-oxadiazolyl-piperidine. The use is also useful for stimulating the function of opioid receptors in a cell in vivo, in an animal, in one of the embodiments of a human, bringing into contact a cell capable of expressing an opioid receptor, in an animal, with a effective amount of a 4-oxadiazolyl-piperidine compound. In one of the embodiments, the use is useful for treating or preventing pain.

or diarrhea in an animal. Brain tissue, spinal cord tissue, immune system cells, gastrointestinal tract cells, and primary afferent nerve cells are examples of tissues and / or cells that are capable of expressing an opioid receptor. This use can be practiced in vitro, for example, as an assay to select cells that express an opioid receptor.

4.4.1 Therapeutic / prophylactic administration and compositions of the invention

[0268] Due to their activity, the 4-oxadiazolyl-piperidine Compounds are beneficially useful in veterinary and human medicine. As described above, the 4-oxadiazolyl-piperidine Compounds are useful for treating or preventing pain or diarrhea in an animal that needs it.

[0269] When administered to an animal, the 4-oxadiazolyl-piperidine Compounds can be administered as a component of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient. The present compositions, which comprise a 4-oxadiazolyl-piperidine Compound, are administered, in one of the embodiments, orally. The compositions of the invention can also be adapted for and administered by any other suitable route, for example, by infusion or bolus injection, by absorption through the epithelial or mucocutaneous coatings (for example, the oral, rectal, and intestinal mucosa , etc.) and can be administered individually or together with another therapeutic agent. Administration can be systemic or local. Several administration systems are known, for example, encapsulation in liposomes, microparticles, microcapsules; capsules, etc., and the same can be used to administer the 4-oxadiazolyl-piperidine Compounds.

[0270] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical, particularly in the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the professional. In most cases, administration will result in the release of a therapeutically effective amount of the 4-oxadiazolyl-piperidine Compounds into the bloodstream.

[0271] In specific embodiments, it may be desirable to administer 4-oxadiazolyl-piperidine Compounds locally. This option can be achieved, for example, by local infusion during surgery, topical application, for example, in combination with a dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of of an implant, said implant being a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.

[0272] Pulmonary administration may also be used, for example, by the use of an inhaler or a nebulizer, and a formulation with an aerosolizing agent, or through perfusion into a pulmonary fluorocarbon or synthetic surfactant. In certain embodiments, the 4-oxadiazolyl-piperidine Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides.

[0273] In another embodiment, the 4-oxadiazolyl-piperidine Compounds can be administered in a vesicle, in particular a liposome (see Science 249: 1527-1533 (1990), of Langer, and Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989), of Treat et al.).

[0274] In still another embodiment, the 4-oxadiazolyl-piperidine Compounds can be administered in a controlled release system (see, for example, Medical Applications of Controlled Release, supra, vol. 2, pp. 115 to 138 (1984), Goodson). Other controlled release systems described in Langer's study, Science 249: 1527-1533 (1990) can be used. In one of the embodiments, a pump can be used (Langer, Science 249: 1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); and Saudek et al., N. Engl. J. Med. 321: 574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas , J. Macromol. Sci. Rev. Macromol. Chem 23:61 (1983); Levy et al., Science 228: 190 (1985); During et al., Ann. Neurol. 25: 351 (1989); and Howard et al., J. Neurosurg.

71: 105 (1989)). In yet another embodiment, a controlled release system may be located in the vicinity of a target of a 4-oxadiazolyl-piperidine Compound, thus only requiring a fraction of the systemic dose. In other embodiments, the 4-oxadiazolyl-piperidine Compounds may be administered through controlled release or sustained release means or by administration devices that are known to those of ordinary skill in the art. Examples include, but are not limited to, the corresponding ones described in U.S. Pat. No.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566. Such dosage forms can be used to provide a slow or controlled release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations, known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the 4-oxadiazolyl-piperidine Compounds. Thus, the invention encompasses individual unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled release.

[0275] The present compositions may optionally comprise a suitable amount of a pharmaceutically acceptable excipient with a view to providing the form corresponding to an administration suitable for the animal. Such pharmaceutical excipients may be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients may be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. Additionally, auxiliary agents, stabilizers, thickeners, lubricants, and colorants can be used. When administered to an animal, pharmaceutically acceptable excipients are preferably sterile. Water is a particularly useful excipient when the 4-oxadiazolyl-piperidine compound is administered intravenously. As liquid excipients, particularly for injectable solutions, saline solutions and aqueous solutions of dextrose and glycerol can also be used. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol and the like. The present compositions, if desired, may also contain small amounts of wetting or emulsifying agents, or pH buffering agents.

[0276] Pharmaceutically acceptable carriers or excipients suitable for intravenous administration of the 4-oxadiazolyl-piperidine Compounds include, but are not limited to, normal saline (approximately 0.9%), polyethylene glycol ("PEG ”) Between approximately 25 and approximately 30% diluted with saline or water, and hydroxypropyl-cyclodextrin between approximately 2 and approximately 30% diluted with water. In one embodiment, compositions for intravenous administration comprise the compound dissolved in sterile isotonic aqueous buffer. When necessary, the compositions may also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic such as lidocaine to reduce pain at the injection site. In general, the ingredients are supplied either separately or mixed together in a unit dosage form, for example, as a dry lyophilized powder or a water-free concentrate in a hermetically sealed container such as a blister or an envelope indicating The amount of active agent. When the 4-oxadiazolyl-piperidine Compounds must be administered by infusion, they can be dispensed, for example, from an infusion bottle containing saline solution or sterile pharmaceutical grade water. When the 4-oxadiazolyl-piperidine Compounds are administered by injection, a vial of sterile water for injection or saline can be provided so that the ingredients can be mixed before administration.

[0277] Among the pharmaceutically acceptable carriers or excipients suitable for intraperitoneal administration of the 4-oxadiazolyl-piperidine Compounds include, but are not limited to, normal saline (approximately 0.9%), PEG between approximately 25 and about 30% diluted with saline or water, propylene glycol (PG) between about 25 and about 30% diluted with saline or water, and hydroxypropyl � – cyclodextrin between about 2 and about 30% diluted with water .

[0278] Among pharmaceutically acceptable carriers or excipients suitable for subcutaneous and intramuscular administration of the 4-oxadiazolyl-piperidine Compounds include, but are not limited to, water, normal saline (approximately 0.9%), PEG between about 25 and about 30% diluted with saline or water, and PG between about 25 and about 30% diluted with saline or water.

[0279] Pharmaceutically acceptable carriers or excipients suitable for oral administration of the 4-oxadiazolyl-piperidine Compounds include, but are not limited to, water, normal saline (about 0.9%), PEG polyethylene glycol between about 25 and about 30% diluted with saline or water, hydroxypropyl-cyclodextrin between about 2 and about 30% diluted with water, PG between about 25 and about 30% diluted with saline or water, and methylcellulose between about 1 and about 5% diluted with water.

[0280] Pharmaceutically acceptable carriers or excipients suitable for intracerebroventricular and intrathecal administration of the 4-oxadiazolyl-piperidine Compounds include, but are not limited to, normal saline solution (approximately 0.9%).

[0281] The present compositions may take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained release formulations, suppositories, aerosols, sprays, suspensions, or any other suitable form for use In one of the embodiments, the composition is presented in the form of a capsule (see, for example, U.S. Patent No. 5,698,155). Remington’s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference, describes other examples of suitable pharmaceutical excipients.

[0282] In one embodiment, the 4-oxadiazolyl-piperidine Compounds are formulated according to routine procedures in the form of a composition adapted for oral administration to an animal, particularly a human being. Compositions for oral administration may be presented, for example, in the form of tablets, losanges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. The orally administered compositions may contain preservatives, coloring agents, and one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin and flavoring agents such as peppermint, gaulteria oil, or cherry, to provide a pharmaceutically palatable preparation. . On the other hand, when they are in the form of a tablet or pill, the compositions may be coated, or otherwise formulated, to retard the disintegration and absorption in the gastrointestinal tract thereby providing sustained action for a prolonged period of time. . Selectively permeable membranes surrounding an osmotically active actuator compound are also suitable for orally administered compositions. In these latter platforms, the fluid surrounding the capsule is absorbed by the actuator compound, which swells to move the agent or the composition of the agent through an opening. These administration platforms can provide an essentially zero-order administration profile as opposed to the peak profiles of immediate release formulations. A temporary delay material such as glycerol monostearate or glycerol stearate can also be used. Oral compositions may include conventional excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one of the embodiments, these excipients are of pharmaceutical quality.

[0283] Pharmaceutical controlled release compositions may have a common goal of improving drug therapy with respect to that achieved by their uncontrolled counterparts. In one of the embodiments, a controlled release composition comprises a minimum amount of a 4-oxadiazolyl-piperidine Compound to cure or control the condition in a minimum amount of time. The advantages of controlled release compositions include prolonged drug activity, reduced dosage frequency, and increased patient compliance. Additionally, controlled release compositions may favorably influence the time of onset of action or other characteristics, such as blood levels of the 4-oxadiazolyl-piperidine Compound, and therefore may reduce the occurrence of adverse side effects.

[0284] In one of the embodiments, the controlled release compositions may initially release an amount of a 4-oxadiazolyl-piperidine Compound that promptly treats or prevents pain or diarrhea, and then gradually releases and continue other amounts of the 4-oxadiazolyl-piperidine Compound to maintain this level of therapeutic or prophylactic effect for a prolonged period of time. To maintain this constant level of the 4-oxadiazolyl-piperidine Compound in the body, the 4-oxadiazolyl-piperidine Compound can be released from the dosage form at a rate that will replace the amount of 4-oxadiazolyl-piperidine Compound that is being metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological or compound conditions.

[0285] The amount of the 4-oxadiazolyl-piperidine Compounds that is effective in the treatment or prevention of pain or diarrhea may depend on the nature or severity of the disorder or condition that causes the pain, and can be determined through of standardized clinical techniques. Additionally, in vitro or in vivo assays can optionally be used to help identify optimal effective dosage amounts. The precise dose to be used can also depend on the desired route of administration, and the degree or severity of pain or diarrhea and it can be determined according to the criteria of the medical professional taking into account the circumstances of each patient and clinical studies. published. Suitable effective dosage amounts are between approximately 10 micrograms and approximately 2,500 milligrams approximately every 4 hours, although typically approximately 100 mg or less. In one of the embodiments, the effective dosage amount is between about 0.01 milligrams and about 100 milligrams of a Compound of 4-oxadiazolyl-piperidine about every 4 hours, in another embodiment between about 0.020 milligrams and about 50 milligrams approximately every 4 hours, and in another embodiment between approximately 0.025 milligrams and approximately 20 milligrams approximately every 4 hours. The dosage amounts described herein refer to total amounts administered; that is, if more than one Compound of 4-oxadiazolyl-piperidine is administered, the effective dosage amounts correspond to the total amount administered.

[0286] When a 4-oxadiazolyl-piperidine Compound is contacted in vitro with a cell capable of expressing an opioid receptor, the amount effective for opioid receptor stimulation will typically be between about 0.01 mg and about 100 mg / L, in one of the embodiments between about 0.1 mg and about 50 mg / L, and in another embodiment between about 1 mg and about 20 mg / L, of a solution or suspension of a pharmaceutical carrier or excipient acceptable. In one embodiment, the opioid receptor is a receptor 1. In another embodiment, the opioid receptor is an ORL-1 receptor. In a further embodiment, the opioid receptor is an opioid receptor 8.

[0287] When a 4-oxadiazolyl-piperidine Compound is contacted in vivo with a cell capable of expressing an opioid receptor, the amount effective for opioid receptor stimulation will typically be between about 0.01 mg and about 100 mg / kg body weight per day, in one of the embodiments between about 0.1 mg and about 50 mg / kg body weight per day, and in another embodiment between about 1 mg and about 20 mg / kg of weight body per day. In one embodiment, the opioid receptor is a receptor 1. In another embodiment, the opioid receptor is an ORL-1 receptor. In a further embodiment, the opioid receptor is an opioid receptor 8.

[0288] Compounds of 4-oxadiazolyl-piperidine can be tested in vitro or in vivo in relation to their ability to treat or prevent pain or diarrhea before use in humans. To demonstrate the safety or efficacy of 4-oxadiazolyl-piperidine Compounds, animal model systems can be used.

[0289] The present methods for treating or preventing pain or diarrhea in an animal may further comprise the administration, to the animal, of an effective amount of a 4-oxadiazolyl-piperidine Compound in combination with an effective amount of another therapeutic agent .

[0290] The present methods for stimulating the function of opioid receptors in a cell may further comprise contacting the cell with an effective amount of another therapeutic agent.

[0291] Examples of other therapeutic agents include, but are not limited to, an opioid agonist, a non-opioid analgesic, a non-steroidal anti-inflammatory agent, an antimigraphic agent, a Cox-II inhibitor, an antiemetic, an � – adrenergic blocker, an anticonvulsant, an antidepressant, a Ca2 + channel blocker, an anticancer agent, an anti-anxiety agent, an agent to treat or prevent an addictive disorder and mixtures thereof.

[0292] The effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is clearly within the scope of qualified professionals to determine the optimal range of effective amounts of the other therapeutic agent. In one of the embodiments of the invention, in which another therapeutic agent is administered to an animal, the effective amount of the 4-oxadiazolyl-piperidine Compound is less than its effective amount would be in the event that the drug was not administered. Another therapeutic agent. In this case, without entering into theoretical discussions, it is believed that the 4-Oxadiazolyl-piperidine Compound and the other therapeutic agent act synergistically to treat or prevent pain or diarrhea.

[0293] Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodin, alphaprodin, anileridine, benzylmorphine, becitramide, buprenorphine, butorphanol, clonitacene, codeine, desomorphine, dextromoramide, dezocine, diazocine, diazocine, dezocine dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafethyl butyrate, dipipanone, eptazocine, ethoheptacin, ethylmethylthiambutene, ethylmorphine, fentanyl etonitacene, heroin, hydrocodone, hydromorphenophonaphamotholone, phenolephenotholonene, phenoethanedinone, limethylmethane, phenoethanoethane, limethylphenotholonene, phenoethanedinone, limenephonaphamotholonene, phenolephenol, phenoxetoloneaphonaphonazenedinone form methazocine, methadone, metopon, morphine, myrofin, nalbuphine, narcein, nicomorphine, norlevorphanol, normetadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenoxone, pheromorphan, phenaprine, pinazoin, propercinine Promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0294] In certain embodiments, the opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0295] Examples of useful non-opioid analgesics include non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, carprofen, murophen, carprofen, carprofen, murophen trioxaprofen, suprofen, aminoprofen, thiaprofenic acid, fluprofen, buclotoxic acid, indomethacin, sulindac, tolmetine, zomepiraco, thiopinac, zidomethacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, diphenamic acid , flufenisal, piroxicam, sudoxicam, isoxicam, and salts thereof, and pharmaceutically acceptable mixtures thereof. Examples of other suitable non-opioid analgesics include the following non-limiting chemical classes of analgesic, antipyretic, non-steroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline and magnesium trisalicylate, salsalate, diflunisal , salicylsalicylic acid, sulfasalazine, and olsalazine; para-aminophenol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (phenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyfentartazone); and alkanones, including nabumetone. For a more detailed description of the NSAIDs, see Analgesic Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout, by Paul A. Insel, in The Pharmacological Basis of Therapeutics of Goodman & Gilman 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed. 1996) and Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II 1196-1221, by Glen R. Hanson (ed. AR Gennaro, 19th ed. 1995) which are incorporated in their entirety herein by reference. In U.S. Patent No. 6,136,839, among other sites, suitable Cox-II inhibitors and suitable 5-lipoxygenase inhibitors, as well as combinations thereof, are described. Cox-II inhibitors include, but are not limited to, rofecoxib and celecoxib.

[0296] Examples of useful antimigraphic agents include, but are not limited to, alpiroprida, dihydroergotamine, dolasetron, ergocornin, ergocorninin, ergocriptine, ergot, ergotamine, flumedroxone acetate, dimethothiazine, lisurid, oxoretin, lomerizetine, lomerizetine, lomerizetine, lomerizetine, lomerizetine, lomerizetine, lomerizetine, lomerizetine, lomerizetine Pizotiline, and mixtures thereof.

[0297] The other therapeutic agent may also alternatively be an antiemetic agent. Useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetyleucine monoethanolamine, alizapride, azasetron, benzquinapidabidamidabidamide, benzquinapidamide , cyclicin, dimenhydrinate, diphenidol, dolasetron, meclycine, metalatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperacin, thioproperacin, tropisetron, and mixtures thereof.

[0298] Examples of useful �-adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufolol, bufolol, bufolol, bufololol bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, chloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol nololol nolprol nolololol nololol nololol nololol oxprenolol, penbutolol, pindolol, practolol, pronetalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

[0299] Examples of useful anticonvulsants include, but are not limited to, acetylfeneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonacepam, decimemide, diethadione, dimetadione, doxenitroin, eterobarbo, etadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mefenitobine, methebitaltine, methebitaltine, methebithythoxyte, methebithoxyte, methebithoxyte, methebithoxyte 5-methyl-5- (3-phenanthryl) -hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassium bromide, pregabalin, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, sultiamo, tetranto na, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide.

[0300] Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, (S) -citalopram, dimethazano, fencamine, indalpine, indeloxacin hydrochloride, nefopam, nomifensin, oxypryptan, oxypertine, paroxetine , sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine , dibencepin, dimetacrine, dotiepine, doxepine, fluacicin, imipramine, imipramine N-oxide, iprindol, lofepramine, melitracene, methapramine, nortriptyline, noxiptyline, opipramol, pizotiline; propicepine, protriptyline, quinupramine, thianeptin, trimipramine, adrafinil, benacticin, bupropion, butacetin, dioxadrol, duloxetine, ethoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hemotophaprine, mothiamphenaprine, miaprinophaprine, michlorophaprine, michlorophaprine, michlorophaprine, michlorophaprine, michlorophaprine, michlorophaprine, michlorophaprine, michlorophaprine, michlorophaprine, michlorophaprine, michlorophaprine, mothophaprin, michlorophaprin, mothophaprin, michlorophaprin, mothophaprin, michlorophaprine, michlorophaprin, michlorophaprin. Oxaflozano, piberalin, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride, sulpiride, tandospirone, tozalinone, tofenacin, toloxatone, tranylcypromine, L- tryptophan, venlafaxine, viloxacin, and cimeldine.

[0301] Examples of useful blockers of the Ca2 + channels include, but are not limited to, bepridil, clentiacem, diltiacem, fendiline, gallopamil, mibefradil, prenylamine, semhotadyl, terodiline, verapamil, amlodipine, aranidipine, barnidipine, barnidipine, barnidipine benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, and perhexiline.

[0302] Examples of useful anticancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronin, adozelesin, aldesleucine, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anastrozole, anastrozole, anastrozole, anastrozole asparaginase, asperlin, azacitidine, azetepa, azotomycin, batymostat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropyrimine, busulfan, cactinomycin, carbopyramine, carbopyramine, carbopyramine, carbopyramine, carbopyramine, carbopyramine, carbopyramine, carbopyramine, carbopyramine, carbopyrimide, carbopyrimide carubicin, carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride , droloxifene, droloxifene citrate, propionate dromostanolone, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erythrozole, esorubicin hydrochloride, estramustine, stramustine sodium phosphate, etoidazole phthalate, etoidazole phthalate, etoidazole, phosphodazole, etoidazole phthalate, etoidazole phthalate, etoidadidazole phthalate, etoidadidazole, phthatodazole, etoidadidazole, phthalate, etoidazole, phosphodazole, etoidazole, phthalate, etoidadiazole, phthalate, ethosidazole, phthalate, ethosidazole, phthalate, ethosidazole, phthalate, ethosidazole, phthalate, ethosidazole, phthalate, ethosidazole, hydrochloride, ethadazorate, chlorohydrate , fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, sodium phostriecin, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmophosin, interleukin II (including recombinant interleukin 2, interferon alpha 2, interferon alpha 2, interferon alpha 2, interferon alpha 2, interferon alpha 2, interferon alpha 2 interferon alfa – 2b, interferon alfa – n1, interferon alfa – n3, interferon beta-I a, interferon gamma-1 b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, sodium lometrexol, Lomustine, losoxantrone hydrochloride, masoprocol, maitansin, mechlorethamine hydrochloride, meges acetate trol, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, sodium methotrexate, metoprine, meturedepa, mitindomide, mitocarcin, mitochromine, mitogiline, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolamine, noopholamic acid, orophenolic acid oxisurane, paclitaxel, pegaspargasa, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, pyroxantrone hydrochloride, plicamycin, plomestane, porphimer sodium, porphyromycin, prednimustine, procarinatin hydrochloride, puromycin, ribomopropyrin, puromycin, ribomoprinozine, puromycin safingol, safingol hydrochloride, semustine, simtrazeno, sodium sparphosate, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talisomycin, tecogalane sodium, tegafur, tisipipyrin, teloxonatrone, teloxonatrone, teloxonatrone, teloxonatrone, teloxonatrone, temoxyatrone, temoxyatrone, temoxyatrone, temoxyatrone, temoxyatrone, temoxyatrone, hydrochloride, temoxyatrone, tephoxyatrone, hydrochloride, safingol, safingol hydrochloride, semustine, simtrazeno, sparphosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talisomycin, tecogalane sodium, tegafur Thioguanine, thiotepa, thiazoturin a, tirapazamine, toremifene citrate, trestolone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uramustine, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vincristine, vincristine vininate Vinepidine Sulfate, Vinglycinate Sulfate, Vinleurosine Sulfate, Vinorelbine Tartrate, Vinrosidine Sulfate, Vinzolidine Sulfate, Vorozol, Zeniplatin, Zinostatin, Zorubicin Hydrochloride.

[0303] Examples of other anticancer drugs include, but are not limited to, 20-epi– 1.25 dihydroxyvitamin D3; 5-ethinyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adocelesin; aldesleucine; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographed; angiogenesis inhibitors; antagonist D; G antagonist; antarélix; anti-dorsal morphogenetic protein – 1; antiandrogen, prostate carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; afidicoline glycinate; modulators of apoptosis genes; apoptosis regulators; apurinic acid; ara – CDP – DL – PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azathyrosine; Baccatin III derivatives; balance; batimastat; BCR / ABL antagonists; benzochlorines; benzoylstaurosporine; beta lactam derivatives; beta-aletine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflato; bropyrimine; budotitan; butionin sulfoximin; calcipotriol; calfostine C; camptothecin derivatives; canaripox IL – 2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorines; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismicin A; colismicin B; combretastatin A4; combretastatin analog; conagenina; crambescidin 816; crisnatol; cryptophycin 8; Cryptophycin A derivatives; curacine A; cyclopentantraquinones; cycloplatam; cipemycin; cytarabine ocphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diazicuone; didemnin B; didox; diethylnorspermine; dihydro-5-azacitidine; dihydrotaxol; 9 – dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebseleno; ecomustine; edelfosine; edrecolomab; eflornithine; elemeno; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; ethanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopyridol; flezelastin; fluasterone; fludarabine; Fluorodaunorunicin Hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantona; ilmophosin; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguano; iododoxorubicin; 4-ipomeanol; iroplact; irsogladin; isobengazol; isohomohalicondrine B; itasetron; jasplaquinolide; kahalalido F; lamelarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitor factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analog; lipophilic peptide disaccharide; lipophilic platinum compounds; lysoclinamide 7; lobaplatin; vermicompost; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecano; lutetium texaphyrin; lysophilin; lytic peptides; maitansin; mannostatin A; marimastat; masoprocol; maspina; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; millimostim; Double stranded RNA with pairing errors; mitoguazone; mitolactol; mitomycin analogs; mitonafide; saporin mitotoxin-fibroblast growth factor; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A + sk of myobacterial cell wall; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor-based therapy 1; mustard-based anticancer agent; Micaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; napharelin; nagrestip; naloxone + pentazocine; napavine; nafterpina; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrulline; O6-benzylguanine; octreotide; ochicenone; oligonucleotides; onapristone; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogs; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxitriol; panomiphene; parabactin; pazeliptina; pegaspargasa; peldesina; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perilylic alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pyrarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complexes; platinum compounds; platinum-triamine complex; sodium porphimer; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; immune modulator based on protein A; protein kinase C inhibitor; protein kinase C inhibitors, in microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; glitter; pyrazoloacridine; polyoxyethylene and pyridoxylated hemoglobin conjugate; raf antagonists; raltitrexed; ramosetron; farnesyl transferase protein inhibitors in ras; ras inhibitors; ras – GAP inhibitor; demethylated reteliptin; rhenium etidronate Re 186; rhizoxin; ribozymes; retinamide RII; rogletimide; rohituquina; romurtida; roquinimex; rubiginone B1; ruboxil; safingol; saintopin; SarCNU; sarcofitol A; sargramostim; Sdi 1 mimetics; semustina; inhibitor 1 derived from senescence; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofirano; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; binding protein for somatomedin; sonermin; sparphic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; Squalamine; stem cell inhibitors; inhibitors of stem cell division; stipulated stromelysin inhibitors; sulfinosine; superactive antagonists of vasoactive intestinal peptides; suradista; suramina; Swainsonin; synthetic glycosaminoglycans; talimustine; iodomethylate (methiodide) from tamoxifen; tauromustine; tazarotene; Tecogalan sodium; tegafur; telurapyridium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastin; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thimopoietin receptor agonist; timotrinan; thyroid stimulating hormone; tin ethyl ethiopurpurine; tirapazamine; titanocene bichloride; topsentina; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; thyrostins; UBC inhibitors; ubenimex; urogenital sinus growth inhibiting factor; urokinase receptor antagonists; vapreotide; varioline B; erythrocyte gene therapy, vector system; velaresol; veramina; vegetables verteporfin; vinorelbine; vinxaltin; vitaxin; vorozole; zanoterone; zeniplatin; cilascorbo; and estimated zinostatin.

[0304] The therapeutic agents useful for treating or preventing an addictive disorder include, but are not limited to, methadone, desipramine, amantadine, fluoxetine, buprenorphine, an opioid agonist, 3-phenoxypyridine, or a serotonin antagonist.

[0305] Examples of useful agents against anxiety include, but are not limited to, benzodiazepines, such as alprazolam, chlordiacepoxide, clonacepam, chloracepate, diazepam, halacepam, loracepam, oxacepam, and pracepam; non-benzodiazepine agents, such as buspirone; and tranquilizers, such as barbiturates.

[0306] Examples of other useful antidiarrheal agents include, but are not limited to, loperamide, diphenoxylate with atropine, clonidine, octreotide, and cholestyramine.

[0307] One of the 4-oxadiazolyl-piperidine Compounds and the other therapeutic agent may act additively or, in one of the embodiments, synergistically. In one of the embodiments, one of the 4-oxadiazolyl-piperidine Compounds is administered simultaneously with another therapeutic agent; for example, a composition comprising both an effective amount of a 4-oxadiazolyl-piperidine Compound and an effective amount of another therapeutic agent can be administered. Alternatively, a composition comprising an effective amount of a 4-oxadiazolyl-piperidine Compound and a different composition comprising an effective amount of another therapeutic agent can be administered simultaneously. In another embodiment, an effective amount of a 4-oxadiazolyl-piperidine Compound is administered before or after the administration of an effective amount of another therapeutic agent so that the benefit of the combination is achieved. In this embodiment, the 4-oxadiazolyl-piperidine Compound is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the 4-Oxadiazolyl-piperidine Compound exerts its preventive or therapeutic effect to treat or prevent pain or diarrhea

[0308] A composition of the invention is prepared by a method comprising mixing a 4-oxadiazolyl-piperidine Compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or excipient. Mixing can be achieved using known methods to mix a compound (or salt) and a pharmaceutically acceptable carrier or excipient. In one of the embodiments, the composition is prepared such that the 4-oxadiazolyl-piperidine Compound is present in the composition in an effective amount.

[0309] The utility of the compounds according to the invention in the treatment of conditions can be demonstrated by binding to receptors 1, ORL-1, 5 and K.

[0310] In one embodiment of the invention, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 300 or less, for binding to opioid receptors 1. In another embodiment, the compounds will have a Ki (nM ) of approximately 100 or less. In yet another embodiment, the compounds will have a Ki (nM) of about 10 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 6 or less. In a further embodiment, the compounds will have a Ki (nM) of about 2 or less. In yet another embodiment, the compounds will have a Ki (nM) of about 1 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 0.1 or less.

[0311] EC50 GTP 1 is the concentration of a compound that provides 50% of the maximum response for the compound in a receptor 1. Typically, the 4-oxadiazolyl-piperidine Compounds having an EC50 GTP 1 (nM) of approximately 5,000 or less stimulates the function of opioid receptors 1. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of approximately 1,000 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 20 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 10 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 8 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 2 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 1 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 0.1 or less.

[0312]% Emax GTP 1 is the maximum effect obtained by a compound with respect to the effect obtained by [D– Ala2, N-methyl – Phe4, Gly – o15] –encephalin (“DAMGO”), a standard agonist 1 . In general, the value of Emax GTP 1 (%) measures the effectiveness of a compound to treat or prevent pain or diarrhea. Typically, Compounds of 4-oxadiazolyl-piperidine will have an Emax GTP 1 (%) greater than 50%. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 1 (%) greater than 75%. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 1 (%) greater than 88%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 1 (%) greater than 100%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 1 (%) greater than 110%. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 1 (%) greater than 115%.

[0313] Typically, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10,000 or less for the ENT-1 receptors. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 2,000 or less. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 1,500 or less. In another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 1,000 or less. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 700 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 100 or less.

In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10 or less.

[0314] The EC50 GTP ORL – 1 is the concentration of a compound that provides 50% of the maximum response for the compound in an ORL – 1 receptor. Compounds of 4-oxadiazolyl-piperidine that have an ECT GTP ENT-1 (nM) of approximately 10,000 or less stimulate the function of ORL-1 opioid receptors. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an ENT GRL-1 (nM) EC50 of approximately

1,000 or less In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an ENT-1 GTP EC50 (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an ORL-1 GTP EC50 (nM) of about 50 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an ENT-1 GTP EC50 (nM) of approximately 10 or less.

[0315] The% Emax GTP ENT-1 is the maximum effect obtained by a compound with respect to the effect obtained by nociceptin, a standard ENT-1 agonist. In general, the value of Emax GTP ORL – 1 (%) measures the effectiveness of a compound to treat or prevent pain or diarrhea. Typically, the 4-oxadiazolyl-piperidine Compounds have an Emax GTP ORL-1 (%) greater than 50%. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP ORL-1 (%) greater than 75%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP ORL-1 (%) greater than 88%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP ORL-1 (%) greater than 100%.

[0316] Typically, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10,000 or less for 5 receptors. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 4,000 or Minor. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 2,500 or less. In another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 1,000 or less. In one embodiment, embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 500 or less. In yet another embodiment, the 4-oxadiazolylpiperidine Compounds will have a Ki (nM) of about 350 or less. In yet another embodiment, the 4oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 250 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10 or less.

[0317] EC50 GTP 8 is the concentration of a compound that provides 50% of the maximum response for the compound in a receptor 8. Compounds of 4-oxadiazolyl-piperidine having an EC50 GTP 8 (nM) of approximately 10,000 or less stimulate the function of opioid receptors 8. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 8 (nM) of about 1,000 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 8 (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 8 (nM) of about 90 or less. In still another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 8 (nM) of about 50 or less. In still another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 8 (nM) of about 25 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 8 (nM) of about 10 or less.

[0318]% Emax GTP 8 is the maximum effect obtained by a compound with respect to the effect obtained by methancephalin. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds have an Emax GTP 8 (%) greater than 50%. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 8 (%) greater than 75%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 8 (%) greater than 90%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 8 (%) greater than 100%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 8 (%) greater than 110%.

[0319] In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10,000 or less for K receptors. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 5,000 or less. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 1,000 or less. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 500 or less. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 400 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 200 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolylpiperidine Compounds will have a Ki (nM) of about 50 or less. In yet another embodiment, the 4oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 1 or less.

[0320] EC50 GTP K is the concentration of a compound that provides 50% of the maximum response for the compound in a K receptor. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP K ( nM) of about 10,000 or less. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP K (nM) of about 5,000 or less. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP K (nM) of about 2,000 or less. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP K (nM) of about 1,000 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP K (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP K (nM) of about 50 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP K (nM) of about 25 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP K (nM) of about 10 or less.

[0321]% Emax GTP K is the maximum effect obtained by a compound with respect to the effect obtained by U69,593. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds have an Emax GTP K (%) greater than 50%. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP K (%) greater than 75%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP K (%) greater than 90%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP K (%) greater than 100%.

4.4.2 Kits

[0322] The invention further encompasses kits that can simplify the administration of a 4-oxadiazolyl-piperidine Compound to an animal.

[0323] One of the typical kits of the invention comprises a unit dosage form of a 4-oxadiazolyl-piperidine Compound. In one of the embodiments, the unit dosage form is provided in a package, in one of the embodiments, a sterile package, which contains an effective amount of a 4-oxadiazolyl-piperidine Compound and a pharmaceutically acceptable carrier or excipient. The kit may further comprise a label or printed instructions explaining the use of the 4-oxadiazolyl-piperidine Compound to treat or prevent pain or diarrhea. The kit may also further comprise a unit dosage form of another therapeutic agent, for example, provided in a package containing an effective amount of the other therapeutic agent. In one embodiment, the kit comprises a container containing an effective amount of a 4-oxadiazolyl-piperidine Compound and an effective amount of another therapeutic agent. Examples of other therapeutic agents include, but are not limited to, the corresponding ones listed above.

[0324] The kits of the invention may further comprise a device useful for administering the unit dosage form. Examples of devices of this type include, but are not limited to, syringes, drip bags, patches, enema bags, and inhalers.

[0325] The following examples are set forth to help understand the invention and obviously should not be considered as limiting specifically the invention described and claimed herein. Those variations of the invention, including the replacement of all equivalents known at present or that are subsequently developed, that would be within the scope corresponding to those skilled in the art, and changes in formulation or minor changes in experimental design , should be considered included within the scope of the invention incorporated herein.

5. Examples

[0326] The following examples refer to the synthesis of Illustrative 4-oxadiazolyl-piperidine Compounds of the present invention as well as to the synthesis of intermediates useful in the synthesis of Illustrative 4oxadiazolyl-piperidine Compounds of the present invention.

5.1 Example 1: synthesis of compound 16 [0327]

Scheme 6

NH2OHHCl K2CO3 / Ethanol

[0328] To a suspension of 50 g (719.53 mmol) of hydroxylamine hydrochloride (Aldrich; St. Louis, MO) in ethanol (500 ml) at 0 ° C was added 99.0 g (719.53 mmol) of potassium carbonate. The resulting suspension was stirred at 0 ° C for 15 minutes and 40.0 g (144.73 mmol) of nitrile 15 (Acros Organics, Morris Plains, NJ) were added. The resulting reaction mixture was stirred at room temperature for 0.5 hours and then refluxed for 12 hours. After this period, the reaction mixture was allowed to cool to room temperature and the inorganic salts were filtered. The filtrate was concentrated with a rotary evaporator and the residue was purified by flash chromatography using an ethyl acetate / hexane gradient as eluent to provide 14.1 g of the amidoxime 16: m / z 310, 1 H NMR (CDCl 3). , 07 (bs, 1 H), 7.47-7.18 (m, 10 H + CHCl3), 4.23 (s, 2 H), 3.46 (m, 2 H), 2.62-2 , 46 (m, 4 H), 2.41-2.30 (m, 2 H), 2.24-2.11 (m, 2 H).

5.2. Example 2: Synthesis of Compound 18

[0329]

Scheme 7

2. Molecular sieves / DMF 90 ° C

[0330] Amidoxime 16 (11.02 g, 55.64 mmol) and NaHCO3 (6.58 g, 78.41 mmol) were suspended in THF (500 ml) under a nitrogen atmosphere. The mixture was cooled to 0 ° C and ethylmalonyl chloride 17 (Aldrich) was added dropwise over 20 minutes (5.6 ml, 6.44 g, 42.77 mmol). The resulting reaction mixture was stirred at 0 ° C for 30 minutes and refluxed for 2 hours. After this period, the reaction mixture was allowed to cool to room temperature and the inorganic salts were filtered. The excess acid chloride in the filtrate was quenched with 50 ml of methanol and the resulting solution was concentrated with a rotary evaporator. The residue was redissolved in DMF (100 ml) and heated at 90 ° C for 10 hours in the presence of 2.0 g of 4 Å molecular sieves. The reaction mixture was cooled to room temperature and volatiles were removed in vacuo to provide a crude sample that was purified by flash chromatography using a gradient of ethyl acetate / hexane as eluent to provide 2.5 g of the oxadiazole 18: m / z 406, 1H NMR (CDCl3) 5 7.41-7.16 (m, 10 H + CHCl3), 4.2 (q, J = 7.23, 2 H), 3.92 (s, 2 H), 3.47-3.43 (m, 2 H), 2.86-2.75 (m, 2 H), 2.74-2.64 (m, 2 H), 2.35-2.17 ( m, 4 H), 1.23 (t, J = 7.02, 3 H).

5.3 Example 3: Synthesis of Compound 20 [0331]

Scheme 8

2. Methanol

[0332] Piperidinyloxadiazole 18 (0.735 g, 1.82 mmol) was dissolved in 100 ml of dichloroethane and 0.3 ml (2.18 mmol) of triethylamine was added under a nitrogen atmosphere. The resulting solution was cooled to 0 ° C and 1-chloroethyl 19 (Aldrich) chloroformate (0.24 ml, 2.18 mmol) was added. The resulting reaction mixture was stirred at 0 ° C for 10 minutes and refluxed for 4 hours. After this period, the volatiles were removed with a rotary evaporator and then the resulting residue was redissolved in 100 ml of methanol. The resulting solution was stirred at reflux for 2 hours and the volatiles were removed using a rotary evaporator. The residue was redissolved in DCM and concentrated again by a rotary evaporator to provide 0.5 g of 20: m / z 316.

5.4 Example 4: Synthesis of Compound 22

[0333]

Scheme 9

[0334] A 50 g (156.7 mmol) portion of 4-Bromo-2,2-diphenyl butyric acid 21 (Aldrich) was suspended in dichloromethane (250 ml). Oxalyl chloride (14.4 ml, 164.5 mmol) was added and the mixture was refluxed under argon for 2 hours. The reaction mixture was cooled to room temperature and then volatiles were removed in vacuo to provide the crude acid chloride, which was used immediately. Sodium carbonate (19.9 g, 188.04 mmol) was dissolved in water (200 mL) and the solution was cooled to -5 ° C (ice-acetone). Aqueous 40% weight / weight 7.9 M dimethylamine (24 mL, 188.04 mmol) was added, followed by toluene (200 mL). The acid chloride in toluene (250 mL) was added for 15 minutes keeping the temperature below 0 ° C during the addition, and the resulting mixture was stirred for an additional 1 hour at this temperature. The organic layer was separated (discarded to remove impurities) and the aqueous layer was extracted with dichloromethane (5 x 500 mL), dried (MgSO4) and the solvent was evaporated in vacuo to leave an off-white solid that was left on the rotary evaporator. at 50 ° C for 20 minutes. The solid was triturated with ethyl acetate (250 mL) to provide 22 (37.5 g, 69.4%) as a white solid: 1 H NMR (CDCl 3) 7.56-7.36 (10 H, m ), 4.86 (2H, t, J = 7.0 Hz), 3.82 (3H, s), 3.47 (2H, t, J = 7.0 Hz), 2.96 (3H, s ).

5.5 Example 5: Synthesis of Compound 23 [0335]

Scheme 10

[0336] To a suspension of 100 g (313,293 mmol) of 4-bromo-2,2-diphenyl butyric acid 21 (Aldrich) in dichloromethane (300 mL) was added oxalyl chloride (328.958 mmol, that is, 164, 48 ml of a 2M solution in dichloromethane (Aldrich)) and the mixture was heated under reflux under argon for 18 hours. The reaction mixture was cooled to room temperature and then volatiles were removed in vacuo to provide the crude acid chloride, which was redissolved in 400 ml of toluene. To a suspension of pyrrolidine (26.74 g, 375.95 mmol) in water (400 ml) was added sodium carbonate (39.84 g, 375.95 mmol), and the resulting solution was cooled to -5 ° C (ice -acetone). The acid chloride in toluene (400 mL) was added for 40 minutes keeping the temperature below 0 ° C during the addition, and the resulting mixture was stirred for an additional 1 hour at this temperature. The organic layer was decanted and the aqueous layer was extracted with dichloromethane (3 x 500 mL), dried (MgSO4) and the solvent was evaporated in vacuo to leave an off-white solid that was left in the rotary evaporator at 50 ° C for 20 minutes. The solid was triturated with ethyl acetate (250 mL) to provide 23 (74.5 g, 63%) as a white solid: 1 H NMR (CDCl 3) 7.57-7.50 (m, 4 H) , 7,487.42 (m, 6 H), 4.92-4.85 (m, 2 H), 4.39-4.32 (m, 2 H), 3.55-3.47 (m, 2 H), 2.91-2.83 (m, 2 H), 2.19-2.08 (m, 2 H), 2,061.94 (m, 2 H).

5.6 Example 6: synthesis of AFL Compound

[0337]

Scheme 11

[0338] A 0.3 ml (4.36 mmol) portion of triethylamine was added to a solution in 1,2-dichloroethane (50 ml) of 20 (0.63 g, 1.82 mmol) at low room temperature nitrogen atmosphere The resulting solution was cooled to 0 ° C and 22 (0.75 g, 2.18 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 hours and at room temperature for 8 hours. After this period, the volatiles were removed with a rotary evaporator and the residue was purified by flash chromatography using an gradient of ethyl acetate / hexane as eluent to provide 0.7 g of AFL: mlz 581, 1H NMR (CD3OD) 5 7.41-7.15 (m, 15 H), 4.11-4.02 (m, 2 H), 3.99-3.92 (m, 2 H), 3.51-3.33 ( m, 2 H), 2.94-2.74 (m, 7 H), 2.63-2.45 (m, 4 H), 2.33-2.16 (m, 5 H), 1, 15-1.09 (m, 3 H).

5.7 Example 7: synthesis of AGE Compound [0339] Scheme 12

Triethylamine / Dichloroethane

[0340] A 2.88 ml (20.72 mmol) portion of triethylamine was added to a solution in 1,2-dichloroethane (50 ml) of 20 (1.75 g, 5.1 mmol) at low room temperature nitrogen atmosphere The resulting solution was cooled to 0 ° C and 23 (2.2 g, 6.0 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 hours and at room temperature for 8 hours. After this period, the volatiles were removed with a rotary evaporator and the residue was purified by flash chromatography using a gradient of ethyl acetate / hexane as eluent to provide 1.2 g of AGE: m / z 607, 1H NMR (CD3OD ) 5 7.34-7.00 (m, 15), 3.96 (q, J = 7.23, 2 H), 3.87 (bs, 2 H), 3.43-3.29 (m , 4 H), 2.84-2.65 (m, 4 H), 2.57-2.39 (m, 4 H), 2.26-2.09 (m, 4 H), 1.56 -1.45 (m, 2 H), 1.43-1.29 (m, 2 H), 1.00 (t, J = 7.23, 3 H).

5.8 Example 8: Synthesis of Compound 24 [0341]

Scheme 13

NH3 / Methanol

[0342] A sample of 0.1 g (0.25 mmol) of 18 was dissolved in 8.0 ml of ammonia in methanol (7N, Aldrich). The resulting solution was stirred at reflux for 40 minutes. The reaction mixture was cooled to room temperature and then volatiles were removed in vacuo to provide a crude sample. The crude product was purified by preparative TLC using 2% methanol in DCM to provide 50 mg of 24 as a white solid: mlz 377, 1H NMR (CDCl3) 5 7.41-7.18 (m, 10 H + CHCl3 ), 7.02 (bs, 1 H), 5.53 (bs, 1H), 3.85 (s, 2 H), 3.46 (bs, 2 H), 2,862.76 (m, 2 H) , 2.73-2.62 (m, 2 H), 2.39-2.15 (m, 4 H).

5.9 Examples 9: synthesis of AFE Compound [0343]

Scheme 14

NH3 / Methanol

[0344] A sample of 0.31 g (0.55 mmol) of AFL was dissolved in 20.0 ml of ammonia in methanol (7N, Aldrich). The resulting solution was stirred at reflux for 40 minutes. The reaction mixture was cooled to room temperature and then volatiles were removed in vacuo to provide a crude sample. The crude product was purified by flash chromatography using a gradient of ethyl acetate / hexane as eluent to give 0.25 g of AFE as a white solid: m / z 552, 1H NMR (CDCl3) 5 7, 46-7.17 (m, 15 H + CHCl3), 6.93 (bs, IH), 5.80 (bs, 1 H), 3.90 (bs, 2 H), 3.66-3.55 (m, 2 H), 2.98 (bs, 3 H), 2.91-2.64 (m, 6 H), 2.62-2.47 (m, 4 H), 2.29 (bs , 3 H).

5.10 Example 10: synthesis of AFX Compound

[0345]

Scheme 15

[0346] A sample of 0.30 g (0.50 mmol) of AGE was dissolved in 20.0 ml of ammonia in methanol (7N, Aldrich). The resulting solution was stirred at reflux for 40 minutes. The reaction mixture was cooled to room temperature and then volatiles were removed in vacuo to provide a crude sample. The crude product was purified by flash chromatography using a gradient of ethyl acetate / hexane as eluent to provide 0.251 g of AFX as a white solid: m / z 578, 1H NMR (CD3OD) 7.44-7.17 (m, 15 H), 3.84 (bs, 2 H), 3.55-3.37 (m, 4 H), 2,992.81 (m, 4 H), 2.68-2.54 (m , 4 H), 2.39-2.21 (m, 4 H), 1.67-1.57 (m, 2 H), 1.54-1.43 (m, 2 H).

5.11 Example 11: binding affinity assays of I and ORL-1 receptors

[0347] The following example will demonstrate that the 4-oxadiazolyl-piperidine Compounds bind to 1 or ENT-1 receptors and, therefore, are useful for treating or preventing pain or diarrhea.

5.11 Materials and methods ORL-1 receptor membrane preparation

[0348] All reagents are obtained in Sigma (St. Louis, MO) unless otherwise indicated. Recombinant HEK-293 cell membranes expressing the human opioid receptor type receptor (ENT-1) (Perkin Elmer, Boston, MA) are prepared by lysing cells in an ice cold hypotonic buffer (2.5 mM MgCl2, 50 mM HEPES, pH 7.4)

(10 mL / 10 cm tray), followed by homogenization with teflon mortar / tissue shredder. The membranes are collected by centrifugation at 30,000 x g for 15 minutes at 4 ° C, and the pellets are resuspended in a hypotonic buffer to a final concentration of between 1 and 3 mg / mL. Protein concentrations are determined using the BioRad protein assay reagent (Hercules, CA) with bovine serum albumin as a standard. Aliquots of the ORL-1 receptor membranes are stored at -80 ° C.

Test procedures for binding of receptors I and ENT-1

[0349] Radioligand dose-shift binding assays for ENT-1 and 1 receptors make use of [3H]-0.1 nM or [3H] -nociceptin-0.2 nM diprenorphine (NEN, Boston, MA) , respectively, with between 5 and 20 mg of membrane / well protein in a final volume of 500 ml of binding buffer (10 mM MgCl2, 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). The reactions are carried out in the absence or presence of increasing concentrations of unlabeled nociceptin (American Peptide Company, Sunnyvale, CA) or naloxone, for ENT-1 and 1, respectively. All reactions are carried out in deep 96-well polypropylene plates for 1 to 2 hours at room temperature. Binding reactions are terminated by rapid filtration in 96-well Unifilter GF / C filtration plates (Packard, Meriden, CT) previously soaked in 0.5% polyethyleneimine using a 96-well tissue collector (Brandel, Gaithersburg, MD) followed for three filtration washes with 500 1L of ice cold binding buffer. Subsequently, the filtration plates are dried at 50 ° C for 2 to 3 hours. A BetaScint scintillation cocktail (Wallac, Turku, Finland) is added (50 gl / well), and the plates are counted using a Packard Top-Count for 1 minute / well. The data is analyzed using the competition curve adjustment functions on a site, in the GraphPad PRISM v.3.0 (San Diego, CA).

Procedure of opioid receptor binding assays 8

[0350] Radioligand dose-shift assays used 0.2 nM [3H] -Naltrindole (NEN; 33.0 Ci / mmol) with between 10 and 20 1g of membrane protein (recombinant delta opioid receptor expressed in CHO cells -K1; Perkin Elmer) in a final volume of 500 µl of binding buffer (5 mM MgCl2, 5% DMSO, 50 mM base Trizma, pH 7.4). In the presence of unlabeled naloxone 25 1M a non-specific binding was determined. All reactions were carried out in deep 96-well polypropylene plates for 1 h at room temperature. Binding reactions were determined by rapid filtration on 96-well Unifilter GF / C filtration plates (Packard) previously soaked in 0.5% polyethyleneimine (Sigma). Collection was performed using a 96-well tissue collector (Packard) followed by five filtration washes with 500 µl of ice cold binding buffer. Subsequently, the filtration plates were dried at 50 ° C for 1 to 2 hours. Fifty 1l / well of scintillation cocktail (MicroScint, Packard) was added and the plates were counted in a Top-Count Packard for 1 min / well.

Procedure of the opioid receptor K binding assays

[0351] Membranes were prepared from recombinant HEK-293 cells expressing the human kappa opioid receptor (kappa) (internally cloned) by lysing cells in ice cold hypotonic buffer (2.5 mM MgCl2, 50 mM HEPES, pH 7.4) (10 ml / 10 cm tray) followed by homogenization with teflon mortar / tissue shredder. Membranes were collected by centrifugation at 30,000 x g for 15 minutes at 4 ° C and pellets were resuspended in hypotonic buffer at a final concentration of between 1 and 3 mg / ml. Protein concentrations were determined using the reagent for BioRad protein assay with bovine serum albumin as a standard. Aliquots of kappa receptor membranes were stored at -80 ° C.

[0352] Radioligand dose-displacement assays used [3H] -U69,593 0.4-0.8 nM (NEN; 40 Ci / mmol) with between 10 and 20 1g of membrane protein (recombinant kappa opioid receptor expressed in HEK 293 cells; internal prep) in a final volume of 200 µl of binding buffer (5% DMSO, 50 mM Trizma base, pH 7.4). In the presence of U69,593 or unlabeled naloxone 10 1M a non-specific binding was determined. All reactions were carried out in 96-well polypropylene plates for 1 h at room temperature. Binding reactions were determined by rapid filtration on 96-well Unifilter GF / C filtration plates (Packard) previously soaked in 0.5% polyethyleneimine (Sigma). Collection was performed using a 96-well tissue collector (Packard) followed by five filtration washes with 2001l ice-cold buffer. Subsequently, the filtration plates were dried at 50 ° C for 1 to 2 hours. Fifty 1l / well of scintillation cocktail (MicroScint, Packard) was added and the plates were counted in a Top-Count Packard for 1 min / well.

5.11.2 Receiver binding data I

[0353] In general, the lower the Ki value, the more effective the 4-oxadiazolyl-piperidine Compounds will be in the treatment or prevention of pain or diarrhea. Typically, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 300 or less for binding to opioid receptors 1. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 100 or less. In another embodiment, the 4-oxadiazolyl-piperidine Compounds of the present invention will have a Ki (nM) of about 10 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds

they will have a Ki (nM) of about 1 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 0.1 or less. The compounds AFL, AGE, AFE, and AFX (ie, Illustrative compound of 4-oxadiazolyl-piperidine) respectively have a Ki (nM) of 1.1, 1.3, 5.9 and 4.8 for binding to opioid receptors 1.

5.11.3 ORL-1 receptor binding data

[0354] Typically, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10,000 or less for the ENT-1 receptors. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 2,000 or less. In another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 1,000 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10 or less.

Receiver Binding Data 8

[0355] Typically, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10,000 or less for 8 receptors. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 4,000 or less. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 2,500 or less. In another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 1,000 or less. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 500 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 350 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 250 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10 or less.

K receptor binding data

[0356] Typically, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10,000 or less for K receptors. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 5,000 or less. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 1,000 or less. In another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 500 or less. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 400 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 200 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 50 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have a Ki (nM) of about 10 or less.

5.12 Example 12: functional activity of GTPyS with opioid receptors I and ENT-1

[0357] The following example will demonstrate that the 4-oxadiazolyl-piperidine Compounds stimulate the function of the 1 or ENT-1 receptors as well as the function of the 8 and K receptors, and therefore, will be useful for treating or preventing pain or diarrhea

5.12.1 Materials and methods

[0358] Functional assays of the [35S] GTPyS are performed using freshly thawed ORL-1 or 1 receptor membranes, as appropriate. The assay reactions are prepared by sequentially adding the following reagents to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice (indicated final concentrations): membrane protein (0.066 mg / mL for the ENT-1 receptor and 0.026 mg / mL for receptor 1), saponin (10 mg / ml), GDP (3 mM) and [35S] GTPyS (0.20 nM; NEN). Aliquots of the prepared membrane solution (190 1L / well) are transferred to flat 96-well polypropylene plates containing 10 1L of 20x concentrated stock solutions of the agonist nociceptin prepared in dimethyl sulfoxide ("DMSO"). The plates are incubated for 30 minutes at room temperature with stirring. The reactions are terminated by rapid filtration on 96-well Unifilter GF / B filtration plates (Packard, Meriden CT) using a 96-well tissue collector (Brandel, Gaithersburg, MD) followed by three filtration washes with 200 1L of buffer. icy junction (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Subsequently, the filtration plates are dried at 50 ° C for 2 to 3 hours. A BetaScint scintillation cocktail (Wallac, Turku, Finland) is added (50 1L / well) and the plates are counted using a Top-Count Packard for 1 minute / well. The data is analyzed using the sigmoid dose-response curve adjustment functions in the GraphPad PRISM v.3.0.

[0359] Functional binding assays of [35S] GTPyS with opioid receptors 8 and K were performed as follows. Kappa or delta opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.026 μg / pl of membrane protein (kappa: internal, delta: Perkin Elmer), 10 μg / ml of saponin, 3 μM GDP and [35S] GTPyS 0.20 nM to binding buffer (100mM NaCl, 10mM MgCl2, 20mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 μl / well) was transferred to flat 96-well polypropylene plates containing 10 μl of 20x concentrated stock solutions of agonist prepared in DMSO. The plates were incubated for 30 min at room temperature with stirring. The reactions were terminated by rapid filtration in a 96-well tissue collector (Packard) and followed by three filtration washes with 200 μl of ice-cold buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). The filtration plates were subsequently dried at 50 ° C for 2 to 3 hours. Fifty µl / well of scintillation cocktail (MicroScint20, Packard) was added and the plates were counted using a Top-Count Packard for 1 min / well.

5.12.2 Function data of the receivers I

[0360] EC50 GTP 1 is the concentration of a compound that provides 50% of the maximum response for the compound in a receptor 1. Typically, the 4-oxadiazolyl-piperidine Compounds having an EC50 GTP 1 (nM) of approximately 5,000 or less stimulates the function of opioid receptors 1. In one embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of approximately 1,000 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 10 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 1 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an EC50 GTP 1 (nM) of about 0.1 or less.

[0361]% Emax GTP 1 is the maximum effect obtained by a compound with respect to the effect obtained by [D– Ala2, N-methyl – Phe4, Gly – o15] –encephalin (“DAMGO”), a standard agonist 1 . In general, the value of Emax GTP 1 (%) measures the effectiveness of a compound to treat or prevent pain or diarrhea. Typically, Compounds of 4-oxadiazolyl-piperidine will have an Emax GTP 1 (%) greater than 50%. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 1 (%) greater than 75%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 1 (%) greater than 88%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP 1 (%) greater than 100%.

5.12.3 Function data of ORL – 1 receivers

[0362] The EC50 GTP ORL – 1 is the concentration of a compound that provides 50% of the maximum response for the compound in an ORL – 1 receptor. Compounds of 4-oxadiazolyl-piperidine that have an ECT GTP ENT-1 (nM) of approximately 10,000 or less stimulate the function of ORL-1 opioid receptors. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an ENT GRL-1 (nM) EC50 of approximately

1,000 or less In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an ENT-1 GTP EC50 (nM) of about 100 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an ORL-1 GTP EC50 (nM) of about 50 or less. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an ENT-1 GTP EC50 (nM) of approximately 10 or less.

[0363] The% Emax GTP ORL – 1 is the maximum effect obtained by a compound with respect to the effect obtained by nociceptin, a standard ENT-1 agonist. In general, the value of Emax GTP ORL – 1 (%) measures the effectiveness of a compound to treat or prevent pain or diarrhea. Typically, the 4-oxadiazolyl-piperidine Compounds have an Emax GTP ORL-1 (%) greater than 50%. In one of the embodiments, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP ORL-1 (%) greater than 75%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP ORL-1 (%) greater than 88%. In yet another embodiment, the 4-oxadiazolyl-piperidine Compounds will have an Emax GTP ORL-1 (%) greater than 100%.

[0364] In the following Table 1, the respective parameters Ki, EC 50 GTP and Emax GTP for receiver 1, ORL-1, 5 and K are summarized for the compounds AFE, AFL, AFX and AGE.

Table 1

Compound

one ENT1

Ki (nM)

EC50 GTP (nM) Emax GTP  Ki (nM) EC50 GTP (nM) Emax GTP

AFE

5.92 16.11 116.50 1,840.74

AFL

1.11 1.04 116.67 695.88 > 20 1m 28.00

AFX

4.82 8.09 90.00 1,293.04

AGE

1.29 2.03 103.33 3,846.20

Compound

5 K

Ki (nM)

EC50 GTP (nM) Emax GTP  Ki (nM) EC50 GTP (nM) Emax GTP

AFE

3,619.47 151.62 1,256.66 44.67

AFL

223.18 84.04 114.5 32.91 1,681.48 52.67

AFX

2,321.18 365.15 3,832.77 41.67

AGE

340.64 21.53 104.33 91.91 703.59 56.00

Claims (29)

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ar1 is phenyl unsubstituted or substituted with one or more R2 groups; Ar2 is phenyl unsubstituted or substituted with one, two, or three R2 groups; Ar4 is phenyl unsubstituted or substituted with one, two, or three R2 groups; G is -H, -C (O) (CH2) nCO2R4, -C (O) (CH2) nR4, - (C1-C5 alkylene) C (O) OR4, or - (C1-C5 alkylene) R5; R1 = -H, -C (O) NH2, -C (O) NHOH, -CO2R4, -CHO, -CN, - (C1-C4 alkyl), -C (O) NH (C1-C4 alkyl), - C (O) N (alkyl C1-C4) 2, -CF3, -CHF2, -CH2F, R2 and R3 are each independently -halogen, -C1-C3 alkyl, -O (C1-C3 alkyl), -NH (C1-C3 alkyl), N (C1-C3 alkyl) 2, -CF3, or -OCF3; R4 = -H, -C1-C10 alkyl, -CH2O (C1-C4 alkyl), -CH2N (C1-C4 alkyl) 2, or -CH2NH (C1-C4 alkyl); R5 = -NH2, -NHSO2R4, -C (O) NH2, -C (O) NHOH, -SO2NH2, -C (O) NH (C1-C4 alkyl), -C (O) N (C1-C4 alkyl) 2, SO2NH (C1-C4 alkyl), -SO2N (C1-C4 alkyl) 2, -H, -OH, -CN, -C3-C8 cycloalkyl, phenyl, naphthyl, antryl, phenanthryl, or heteroaryl (5 to 7 members), not being substituted or being substituted with one or more R2 groups each C3-C8 cycloalkyl, phenyl, naphthyl, antryl, phenanthryl, or heteroaryl (5 to 7 members); m = an integer that goes from 0 to 4; n = an integer ranging from 1 to 4; p = 0 or 1; Y q = an integer ranging from 1 to 6. 2. Compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: Ar3 is phenyl unsubstituted or substituted with one, two, or three R2 groups; Ar4 is phenyl unsubstituted or substituted with one, two, or three R2 groups; G = H, -C (O) (CH2) nC (O) OR4, -C (O) (CH2) nR5, - (C1-C5 alkylene) C (O) OR4, or - (C1-C5 alkylene) R5 ; R1 = -H, -C (O) NH2, -C (O) NHOH, -CO2R4, -CHO, -CN, - (C1-C4 alkyl), -C (O) NH (C1-C4 alkyl), - C (O) N (alkyl C1-C4) 2, -CF3, -CHF2, -CH2F, R2 and R3 are each independently -halogen, -C1-C3 alkyl, -O (C1-C3 alkyl), -NH (C1-C3 alkyl), N (C1-C3 alkyl) 2, -CF3, or -OCF3; R4 = -H, -C1-C10 alkyl, -CH2O (C1-C4 alkyl), -CH2N (C1-C4 alkyl) 2, or -CH2NH (C1-C4 alkyl); R5 = -NH2, -NHSO2R4, -C (O) NH2, -C (O) NHOH, -SO2NH2, -C (O) NH (C1-C4 alkyl), -C (O) N (C1-C4 alkyl) 2, SO2NH (C1-C4 alkyl), -SO2N (C1-C4 alkyl) 2, -H, -OH, -CN, -C3-C8 cycloalkyl, phenyl, naphthyl, antryl, phenanthryl, or heteroaryl (5 to 7 members), not being substituted or substituted with one, two or three R2 groups each C3-C8 cycloalkyl, phenyl, naphthyl, antryl, phenanthryl, or heteroaryl (5 to 7 members); m = an integer that goes from 0 to 4; n = an integer ranging from 1 to 4; p = 0 or 1; Y q = an integer ranging from 1 to 6.

3.

Compound of claim 1 or 2, wherein m = 1 and G = H.

Four.

Compound of claim 1 or 2, wherein R1 is -C (O) NH2, -C (O) NH (C1-C4 alkyl), or -C (O) N (C1-C4 alkyl) (C1- alkyl C4).

5.

Compound of claim 1 or 2, wherein R1 is -CN.

6.

Compound of claim 1 or 2, wherein m = 1, p = 0 and q = 3.

7.

Compound of claim 1 or 2, wherein G = - (CH2) 2NHSO2H.

8.

Compound of claim 1 or 2, wherein G = -CH2C (O) NH2, -CH2C (O) NH (C1-C4 alkyl) or CH2C (O) N (C1-C4 alkyl) (C1-C4 alkyl) , preferably -CH2C (O) NH2.

9.

Compound of claim 1 or 2, wherein G = -CH2C (O) OCH2CH3.

10.

Compound of claim 8 or 9, wherein R1 = -C (O) N (CH3) 2.

eleven.

Compound of claim 8 or 9, wherein R1 is

12.

Compound of claim 1 or 2, wherein G = - (CH2) 2C (O) OCH2CH3.

13.

Compound of claim 1 or 2, wherein G = - (CH2) 4C (O) OCH2CH3.

14.

Compound of claim 1 or 2, wherein p = 1.

fifteen.

Composition comprising a compound of claim 1 or 2 and a pharmaceutically acceptable carrier or excipient.

16.

Composition of claim 15, further comprising at least one compound selected from the group consisting of an opioid analgesic, a non-opioid analgesic, and an antiemetic agent.

17.

Method for preparing a composition, the method comprising mixing a compound of claim 1 or 2 and a pharmaceutically acceptable carrier or excipient.

18.

Kit comprising a package containing the composition of claim 15, preferably further comprising an antidiarrheal agent.

19.

Use of a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, in the preparation of a medicament in the treatment or prevention of pain or diarrhea.

twenty.

Use according to claim 19, further comprising administering an effective amount of at least one compound selected from the group consisting of an opioid analgesic, a non-opioid analgesic, and an antiemetic agent.

twenty-one.

Compound of claim 1, described by the following formula

or a pharmaceutical salt thereof. 22. Compound of claim 1, described by the following formula or a pharmaceutical salt thereof. 23. Compound of claim 1, described by the following formula

or a pharmaceutical salt thereof.

24. Compound of claim 1, described by the following formula

or a pharmaceutical salt thereof.

25.

Use of a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, as a medicament.

26.

Use of a compound for claim 1 or 2 or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for stimulating the function of opioid receptors in a cell, comprising bringing into contact a cell capable of expressing an opioid receptor. with an effective amount of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, for the treatment of pain or diarrhea.

27.

Use according to claim 26, wherein the receptor is selected from the group consisting of an opioid K receptor, an opioid receptor 1, an opioid receptor 5 or an ORL-1 receptor for the treatment of pain or diarrhea.

28.

Compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, for the treatment of pain or diarrhea.

29.

Compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, for the stimulation of a function of opioid receptors in a cell, for the treatment of pain or diarrhea.